The Newsletter for the Society for Medicines Research

Volume 8 Issue 1 January 2002

The Role of Sodium Channels in Disease Case Histories Meeting by Alan M. Palmer and Nick Carter by the SMR Committee

The September 2001 symposium convulsant that is now used widely The Society for Medicines Research focused on the role of sodium channels (lamotrigine) and an impressive neuro- (SMR) held a one-day meeting on in disease. Native sodium channels protective agent that is in clinical trials Case Histories in on 6 exist as polypeptide multimers of an for stroke (sipatrigine). The December 2001 at the National Heart α-subunit (260kD) and subsidiary and development of the next generation of and Lung Institute in London. These smaller β-subunits (generally three sodium channel blockers will be meetings have been organised by the β β β greatly facilitated by an elaboration of SMR biannually for many years and different subunits: 1, 2 and 3). The α-subunits are structurally diverse, the pharmacology of the various this latest meeting of the series arising from multiple sodium channel isoforms, which itself is dependent attracted over 100 registrants. The genes and alternative splicing events. upon the existence of reliable, rapid and purpose of these meetings is Recent progress has led to a good high-throughput assays for sodium educational: it allows those interested understanding of the molecular channel activity. in drug discovery to hear succinct structure of sodium channels, how they accounts of recent successes. There work and the significance of their Introduction was no overall linking theme between expression in particular cell types. Sodium channel activity is intrinsic to the talks other than that each success neurotransmission and therefore has a This, coupled with experimental studies story has led to the introduction of a linking particular isoforms with central role in normal neuronal new and improved product for particular disease states and the function. Sodium channels are highly therapeutic use. The drug discovery selective molecular pores, the opening discovery of distinct human sodium stories covered in the meeting were channelopathies (specific mutations in and closing of which shape membrane extremely varied and, put together, specific isoforms that cause a variety of potential changes and give rise to emphasised that each successful story characteristic action potentials. Over- diseases, including paralysis, long QT is individual and special. This activation of sodium channels can lead syndrome and epilepsy), is beginning to meeting is also special for the SMR in reveal how particular sodium channel to neuronal dysfunction. Thus, the that it presents its ‘SMR Award for subtypes underlie specific pathologies. depolarisation of plasma membranes Drug Discovery’ in recognition of that occurs in acute brain injury (such as All this provides great potential for the outstanding achievement and development of new therapies. The first stroke and traumatic brain injury) or contribution in the area. These generation of sodium channel blockers over-stimulation of certain neurones successes were considered in the (such as that occurring in chronic pain has led to a broad-spectrum anti- context of the high risk of failure in (continued on page 4) drug discovery and the rarity of successful new product introduction. Malcolm Duckworth: The programme included two New SMR Chairman unrelated talks on chiral drugs both of Dr Malcolm Duckworth has taken over as the which have a currently marketed Chairman of the Society for Medicines racemate — single isomer switches. Research. All his industrial life has been Dr Sverker von Unge (AstraZeneca, spent in research in the pharmaceutical Sweden) related the account of the industry. He started as a medicinal chemist development of nexium with Beecham Pharmaceuticals in the late (esomeprazole) (2), the S-enantiomer 1970s at the Walton Oaks Research Site in of the proton pump inhibitor, Losec Surrey and continued in that discipline with SmithKline Beecham where he gained (omeprazole) (1), the top-selling anti- experience in metabolic, anti-infective and ulcer drug. To understand why CNS disease areas. His emerging interest in esomeprazole was developed, it was genomics led to him to move into important to know the origin and Bioinformatics in 1997. He is currently head mechanism of action of the racemate. of a bioinformatics group in Glaxo- Omeprazole was discovered in the late SmithKline with responsibility for 1970s as a blocker of gastric-acid supporting the European Centres of strong supporter of the SMR. He joined the secretion and came from a medicinal Excellence for Drug Discovery, and is based Committee in 1995 and became the Honorary at Harlow in Essex. Secretary in 1998.• chemistry programme based on a Dr Duckworth has always been a (continued on page 2) page 2

(continued from page 1) 2000. Committee pyridine-based thioamide. Elucidation The second isomer talk was of the mechanism of action of given by Dr Robert Gristwood Secretariat omeprazole showed that it was a (Arachnova Ltd) who described the Lilian Attar, Triangle House, prodrug which relies on a protonated story behind ChirocaineTM Broomhill Road, London SW18 4HX, form of the compound reacting with the (levobupivacaine) (3), the single-levo Tel: 020 8875 2431; e-mail: enzyme H+/K+ ATPase. The basicity of enantiomer of the racemic drug secretariat@ socmr.org. the pyridine is important. While the bupivacaine (4), currently the leading free base is acid labile, if present in long-acting local anaesthetic. Chairman sufficient quantity, it can penetrate the Chirocaine was developed through to Dr D. Malcolm Duckworth, Glaxo- parietal cells of the gastric mucosa registration by Ltd (now SmithKline, New Frontiers Science wherein the protonated form made part of Group) and is currently Park, Third Avenue, Harlow, Essex inside the cells accumulates, because of marketed in 11 countries (the first in CM19 5AW; fax: 01279 622929. much-reduced permeability. In a 2000), including the US. It represented reversible process, a reactive the first new chemical entity from a Vice-chairman intermediate is formed from the ‘UK biotech company’ to be approved Dr David Cavalla, Arachnova Ltd, St protonated omeprazole, which reacts in the US by the FDA in 1999. Dr John’s Innovation Centre, Cambridge with a mercapto group of the enzyme. Gristwood gave some background to CB4 0WS; fax: 01223 722 577. Omeprazole, therefore, has a fast mode single-isomer switches and reasons why of action at the target, which leads to they should be considered. Some Honorary Secretary high selectivity and a long duration of advantages may be to give drugs that Dr Alan M Palmer, Vernalis, action. However, improvements were are less toxic, or more potent, or that Oakdene Court, 613 Reading Road, sought in pharmacokinetic profile, in have cleaner pharmacokinetic profiles. Winnersh, Wokingham RG41 5UA; terms of less inter-individual variability Over 500 drugs currently exist as fax : 0118 989 9300. and greater resistance to gastric juice. racemates but possibly only 5% are Several hundred compounds suitable. Unfortunately, the properties Honorary Treasurer were synthesised in the search but none of the enantiomers are not predictable Dr Mark A Giembycz, Department of could surpass omeprazole. An ongoing from the racemates, for example, liver Thoracic Medicine, National Heart and project was to test fully both toxicity is seen with an enantiomer of Lung Institute, Dovehouse Street, Lon- enantiomers since either might meet the labetalol and QT prolongation is don SW3 6LY; fax: 020 7351 5675. requirements for a backup compound. observed for R-fluoxetine. With improved methods for The story behind Chirocaine Committee synthesising large quantities of each provided an interesting strategic Dr Richard Armer, Organon isomer, it was shown that both isomers contrast to the nexium story. Adopting Laboratories Ltd; fax: 01638 736187. have identical enzyme inhibitor potency a systematic evaluation of racemic drug in vitro, but in vivo, in rats, the R- opportunities, bupivacaine was Dr Kate Brown, Imperial College of isomer was more potent and had higher identified as a candidate for a single Science and Technology; fax: 020 7594 bioavailability compared with the S- isomer switch. The decision to proceed 5207. isomer. Alkaline salts of the isomers with development in 1993 was based on Prof Nick Carter, St George’s were found to be crystalline which was Chiroscience’s expertise in single- Hospital Medical School; fax: 020 also advantageous for future clinical isomer synthesis and development, the 8725 5967. studies. Surprisingly, in man, there was hypothesis that levobupivacaine had a reversal of isomer superiority with the similar local anaesthetic activity to the Dr Simon Hodgson, GlaxoWellcome; S-isomer showing 90% inhibition of racemate but lower cardiotoxicity in fax: 01438 763615. stimulated acid secretion compared with man, and the ability to protect the 25% for the R-isomer after 15mg p.o., product commercially through use-and- Dr Ian Morris, University of Man- day 7. In addition, the clearance of the process patents despite the absence of a chester; fax: 0161 275 5600. S-isomer was slower by approximately substance-of-matter patent. In order to Prof Clive Page, King’s College one-third of the R-isomer. Individual evaluate data clearly the metabolism of London; fax: 020 7848 6097. differences were explained by chiral drugs has to be considered as it variations in the metabolic enzyme can often lead to racemisation or chiral Prof Barry Potter, Dept of Pharmacy CYP2C19. This form of the enzyme inversion, which would negate the and Pharmacology, University of Bath; does not exist in the rat. In summary, advantages. In the case of fax: 01225 826114. nexium is superior to omeprazole levobupivacaine, the compound is because of advantageous metabolism, metabolised to inactive species rather Dr Sandy Pullar, Lilly Research acid control is greater, faster, more than to the dextro isomer. Evidence Centre; fax 01276 853 525. sustained and more predictable, thus from animal species showed that Dr Peter Warne, e-mail: Peter. improving the clinical efficacy. To give Chirocaine is less toxic than the [email protected]. some idea of the time scale, the racemate, e.g. less effective in isolated omeprazole project first began in 1972 hearts, less active on myocardial Dr Robert Williams, Prolifix Ltd; fax: and nexium was launched in Sweden in (continued on page 3) 01235 443 7344. page 3

Elidel is cell selective and highly effective in animal models of skin , such as the pig model of allergic contact dermatitis. This is predictive for humans as the skins of the two species are very similar. Unlike corticosteoids, Elidel does not induce skin atrophy. With respect to tacrolimus, Elidel is more lipophilic with a higher affinity for skin. Thus, it distributes more preferentially in skin, but because it permeates through it only slowly, it has a reduced systemic side-effect profile. It is much less immuno-suppressive and overall has an improved therapeutic window of anti-inflammatory to immuno-suppressive profile. There is minimal systemic absorption, regardless of age, and Elidel cream 1% shows rapid relief of atopic dermatitis and pruritus, suitable for short- and long-term treatment in adults, children and babies. Treatment success is maintained over six months. Orally, pimecrolimus has also been shown to be effective, safe and well tolerated in patients with moderate to severe plaque psoriasis. By integrating disease knowledge with pharmaco-genomic gene expression technology, it was possible to link mRNA expression with therapeutic progress, and also find potential indicators of side-effects, by profiling and perceived risks with bupivacaine. blood samples following oral Elidel (continued from page 2) treament. One hundred and sixty-three sodium and potassium channels. Phase Professor Anton Stuetz genes were identified with consistent I studies in humans (clinical proof-of- ( Research Institute, behaviour related to psoriasis principle studies) looking at Vienna) described the discovery and pathophysiology, such as down- cardiovascular parameters after development of pimecrolimus (Elidel, regulation of genes associated with intravenous administration confirmed SDZ ASM 981) (5), a new skin- leucocyte activation, lymphocyte the preclinical evidence that the levo selective option for topical and oral infiltration and inflammatory process. isomer was less toxic than the racemate treatment of inflammatory skin No changes in gene expression were while in an efficacy study (ulnar nerve diseases. Current treatments for observed that might be linked to drug- blockage) there were no differences in inflammatory skin diseases such as related side-effects. Currently Elidel anaesthetic potency. Following corticosteroids, cyclosporin-A or cream is under review for registration successful Phase II studies, Chirocaine tacrolimus (FK 506), have a number of worldwide for topical treatment and is was licensed for a number of routes of deficiencies, most notably induction of undergoing further evaluation as an oral clinical administration (e.g., epidural, skin atrophy, a lack of topical effect or treatment. intrathecal, peripheral block). Phase III systemic side-effects. Pimecrolimus The 2001 SMR Award for efficacy studies were completed in was the successful outcome of a Drug Discovery was presented to the 1996. Chirocaine was approved by the structure–activity relationship study of key members of the team that led to the FDA without the black box warning the natural product macrolactam discovery of rosiglitazone (Avandia, regarding cardiovascular liability then ascomycin. It binds in low nanomolar BRL 49653) (6), which was developed associated with bupivacaine. It has not, concentrations to macrophilin-12 and for the treatment of type 2 diabetes. however, totally displaced bupivacaine. inhibits calcineurin, a phosphatase, Michael Cawthorne, Stephen Smith, It does cost approximately 50% more preventing phosphorylation of a Barrie Cantello, Richard Hindley than the racemate in the UK so transcription factor ultimately leading and David Haigh, scientists from the increased usage will depend on to a down regulation of inflammatory original Beecham Pharmaceuticals perceived cost-benefit considerations cytokines in T-cells, such as IL4. (continued on page 10) page 4

(continued from page 1) without affecting normal synaptic was considered that the efficacy of both states) leads to excessive sodium transmission probably underlies the compounds was mediated by inhibition channel activity. good tolerability of sodium channel of the release of the excitatory amino The pharmacology of sodium blocking drugs. The prototypic acids aspartate and glutamate. channels is currently very rudimentary, example of first-generation sodium However, John Garthwaite (who joined since they are distinguished on the channel blockers is the broad- Wellcome as head of neuroscience in basis of sensitivity to a toxin derived spectrum anticonvulsant lamotrigine 1992, and is now at the Wolfson from puffer fish, tetrodotoxin. It is now (Lamic-talTM) which is now used Institute for Biomedical Research, known that native sodium channels widely to treat epilepsy. Lamotrigine University College London) reasoned exist as polypeptide multimers, may also have utility in the treatment that the mechanism of action was not comprising a large (260kD) α-subunit of other disorders, e.g. bipolar precisely defined since both compounds and smaller (33–36kD) modulatory β- disorder. Another prototypic sodium blocked veratrine-evoked release of subunits (there are at least three channel blocker, with a different EAAs, but not potassium-evoked β β β efficacy profile, is sipatrigine release. The fact that veratrine evokes different subtypes: 1, 2 and 3). The α-subunits are structurally diverse, (BW619C89), which is derived release by opening sodium channels arising from multiple sodium channel chemically from lamotrigine. suggested that it is sodium channel genes and alternative splicing events Sipatrigine is a neuro-protective agent blockade that was underlying the (see Table 1). Recent progress has led now in clinical trials for stroke. The efficacy of both lamotrigine and to a good understanding of the development of the next generation of sipatrigine. This was then demonstrated molecular structure of sodium channels, sodium channel blockers will be directly by electro-physiological studies greatly facilitated by elaboration of the of cells expressing recombinant Na 1.2 how they work and the significance of v their expression in particular cell types. pharmacology of the various isoforms sodium channels (Xie and Garthwaite, This, coupled with the therapeutic of sodium channel subunits, which 1996). utility of sodium channel blockers for a itself is dependent upon the existence Professor Garthwaite went on number of disorders and the elucidation of reliable, rapid and high-throughput to describe how sodium channel of distinct sodium channelopathies, is assays for sodium channel activity. blockers have great potential as beginning to reveal how particular The presentations developed three therapies for disorders associated with sodium-channel subtypes are linked to themes: neuro-degeneration since they protect different disease states. All this 1. The first generation of sodium both grey and white matter. He pointed provides great potential for the channel blockers: lamotrigine and out how the discovery of ways to development of new therapies and sipatrigine. protect the brain and spinal cord from underlines the attractiveness of this 2. Relating structure to function. degeneration in acute and chronic stress under-exploited class of compounds. 3. The prospects for the next gener- conditions represents one of major The discovery of compounds ation of sodium channel blockers. challenges facing neuroscience. that block over-activated sodium Progress is clearly dependent upon channels, while permitting normal First-generation sodium channel understanding the underlying currents of sodium ions, has provided blockers mechanisms, which are likely to be The two prototypic sodium channel the basis to develop sodium channel either specific to a particular disease blockers are the phenyltriazine lamo- blockers for the treatment of CNS state (for example, genetic trigine and the phenylpryimidine disorders, such as stroke, traumatic susceptibility, viral ) or more sipatrigine (see Figure 1). Both were brain injury and pain; sodium channel general (for example, those leading to synthesised and developed by blockers may also be useful in treating cell death by necrosis or apoptosis). A Wellcome scientists at Beckenham. other disorders. The ability of sodium step forward in understanding what Lamotrigine was synthesised as part of channel blocking drugs to attenuate might be one of the more general a programme to discover new abnormal activity of sodium channels mechanisms was achieved over two antifolates and shown to have decades ago with the realisation that anticonvulsa glutamate is not only the main Cl Cl Cl nt efficacy. excitatory neurotransmitter in the brain, Sipatrigine but also a powerful neurotoxin to many arose from a different CNS neurones. This work Cl Cl programme then led to the formulation of the to develop ‘excitotoxic’ hypothesis wherein NH2 NH2 analogues of excessive glutamate receptor activation N lamotrigine contributed to (or caused) neuronal cell N N N N and was death. Demonstrations that antagonists subsequently acting on glutamate receptors of both shown to the NMDA and AMPA subclass were NH2 NH2 have neuro- protective in animal models of stroke protective and trauma added weighty evidence in Lamotrigine Sipatrigine efficacy. At support of this hypothesis. The the time it (continued on page 5) Figure 1 Prototypic first-generation sodium-channel blockers page 5

(continued from page 4) multiple failures of this approach in Table 1 Mammalian sodium-channel α-subunits clinical trials in stroke victims, Type Former Genbank Gene symbol Chromosomal Splice Primary however, demands a rethink. It can be name numbera location variants tissues c argued, with some justification, that the Nav1.1 rat I X03638 (r) SCN1A Mouse 2 Nav1.1a CNS hypothesis was never subjected to HBSCI X65362 (h) Human 2q24 PNS proper experimental testing in humans GPBI AF003372(gp) SCN1A (for example, inadequate dosing or too Nav1.2 rat II X03639 (r) SCN2A Mouse 2 Nav1.2a CNS long a delay prior to drug HBSCII X61149 (r) Human 2q23-24 administration; see Dawson et al., HBA X65361 (h) 2001). But another factor is that, to a M94055 (h) greater or lesser extent, neuro- Nav1.3 rat III Y00766 (r) SCN3A Mouse 2 Nav1.3a CNS Human 2q24 Nav1.3b degenerative disorders affect both Nav1.4 SkM1, µ-1 M26643 (r) SCN4A Mouse 11 Skeletal neurones in the grey matter and their muscle axons running in the white matter. M81758 (h) Human 17q23-25 Nav1.5 SkM2 M27902 (r) SCN5A Mouse 9 Uninnervated Moreover, the human brain has skeletal disproportionately more white matter muscle, hear than a rodent’s. Hence, a better H1 M77235 (h) Human 3p21 Nav1.6 NaCh6 L39018 (r) SCN8A Mouse 15 Nav1.6a CNS, PNS approach has to be one that is capable PN4 AF049239 (r) Human 12q13 of protecting both grey and white Scn8a AF049240 (r) matter. CerIII U26707 (m) Voltage-gated Na+ channels AF049617 (m) AF050736 (h) are expressed at the surface of all AF225988 (h) neuronal elements (dendrites, somata AF003373 (gp) and axons). Maintenance of ionic Nav1.7 NaS U35238 (rb) SCN9A Mouse 2 PNS homeostasis in the face of continuous hNE-Na X82835 (h) Human 2q24 Schwann cel entry of Na+ into the cytoplasm PN1 U79568 (r) AF000368 (r) represents a major pathway for energy Nav1.8 SNS X92184 (r) SCN10A Mouse 9 DRG expenditure in the CNS. When energy PN3 U53833 (r) Human 3p22-24 is lacking (for example, because of poor NaNG Y09108 (m) blood perfusion) failure of Na+ (and U60590 (d) therefore K+) homeostasis is expected Nav1.9 NaN AF059030 (r) SCN11A Mouse 9 Nav1.9a PNS SNS2 AJ237852 (r) Human 3p21-24 to be one of the first consequences, with PN5 AF118044 (m) many secondary ones to follow should NaT AB031389 (m) the situation persist. With excito- SCN12A AF126739 (h) toxicity in full flurry, little thought was AF188679 (h) AF109737 (h) given to the possible importance of this AF150882 (h) pathway in neuro-degeneration, even Nax Nav2.1 M91556 (h) SCN7A Mouse 2 heart, uterus though there were already clues in the skeletal + muscle, literature that the classical Na channel astrocytes, inhibitor, tetrodotoxin (TTX), had DRG b neuro-protective properties in vitro and Na-G M96578 (r) SCN6A Human 2q21-23 SCL11 Y09164 (r) in vivo. The identification of Nav2.3 L36179 (m) compounds that act in a voltage- and a The letter in parentheses after each accession number indicates the species of origin for the sequence, as follows: use-dependent manner on Na+ channels h, human; r, rat; rb, rabbit; m, mouse; gp, guinea pig; d, dog. b This gene was originally assigned symbols SCN6A and SCN7A, which were mapped in human and mouse, (rather like some anticonvulsants) and respectively. The two most likely represent the same gene, and the SCN6A symbol will probably be deleted. protect grey matter at least as c DRG, dorsal root ganglion; PNS, peripheral nervous system; CNS, central nervous system (modified from Goldin effectively as glutamate antagonists, et al., 2000). provided additional evidence. the same protein, it appears possible to channels are open compared to their Moreover, these compounds inhibited provide dual protection of grey and resting state. However, inactivation ischaemia-induced glutamate release, white matter, at least in ischaemia. does proceed at a finite rate whenever consistent with a primary action to Whether any particular Na+ channel membranes are depolarised from about preserve ionic homeostasis. subtype dominates in the pathogenesis -140 mV. Drugs that interact with Na+ Furthermore, investigation into the of the damage remains unknown but channels to block ion flux cause the mechanism of ischaemic damage to channels that inactivate slowly on channels to inactivate to a greater white matter axons highlighted the depolarisation may be especially extent and with smaller depolarisations central role played by Na+ channels in significant. than they would normally exhibit. The triggering the axonopathy. In this case, Na+ channels cycle between relatively slow off-rate of drugs such as irreversible damage appears to be the resting, activated and inactivated phenytoin means that there is an result of a secondary Ca2+ overload of states. Inactivation proceeds many accumulated block with repeated the axoplasm. Hence, through targeting thousands of times faster when (continued on page 6) page 6

channel blockers, has in stroke patients using diffusion and been shown to be perfusion weighted MRI to determine effective in a number of the effect of sipatrigine on infarct size models of acute brain as a surrogate marker. A dose- O injury (see Table 2). The escalation study has commenced as a OH spectrum of activity and prelude to this study. N CH the amount of efficacy Sipatrigine has commenced 3 achieved is impressive, development for clinical use. particularly when Preclinical safety and toxicology compared with studies showed a profile of activity CH3 CH compounds that block satisfactory for further development. 3 the N-methyl-D- Phase I intravenous studies in healthy CH 3 aspartate (NMDA) volunteers reported no serious adverse receptor. A number of events. In a series of safety and Figure 2 BIII890CL, which is in clinical trials for stroke Na+ channel blockers tolerance Phase II studies in stroke have entered clinical patients who received iv infusions of (continued from page 5) trials for stroke, including sipatrigine, sipatrigine, the main adverse events depolarisations (use-dependent block). lifarizine, fosphenytoin (a phosphate observed were hallucinations and This means that, in the case of ester prodrug of phenytoin) and vomiting. Overall, therefore, therapeutically relevant concentrations lubeluzole. sipatrigine has been shown to be of phenytoin (8 µM), channel block is Since Terry Smith (CeNeS clinically acceptable in healthy only significant if cells remain Ltd) was not able to attend the meeting volunteers and stroke patients. From depolarised for at least five seconds. (or find a suitable replacement from these data, there is good evidence that This may explain why phenytoin does his company) Alan M Palmer sipatrigine crosses the blood–brain not alter normal action potentials or (Vernalis) presented Dr Smith’s slides barrier. There are insufficient data, excitatory synaptic potentials — these describing the clinical development of however, to identify evidence of events last for less than 200ms. sipatrigine for the treatment of stroke. efficacy or the optimal dose of Sustained depolarisation, during In addition to blocking Na+ channels, sipatrigine with which to establish such ischaemia or seizures, greatly enhances sipatrigine has been shown to block a efficacy. To try to answer these the blocking action of phenytoin and number of subtypes of Ca2+ channels questions, a clinical trial has similar drugs. Hodgkin and Huxley (McNaughton et al., 2000), which may commenced using MRI perfusion/ (1952) first described the three-state well contribute to the neuro-protective diffusion mismatches to investigate the model for Na+ channels, and a theory to efficacy of this compound. effects of sipatrigine on a surrogate explain use-dependent blockade of ion Several Phase II studies with marker, namely the change in size of an channels, termed the ‘modulated this compound were completed by ischaemic lesion in the cortex. receptor theory’, has been developed Wellcome and preliminary based on their observations. This information on safety suggests that the Lamotrigine for epilepsy theory assumes that Na+ channel development of visual hallucinations Dr Malcolm Nobbs (GlaxoSmithKline) blockers bind different channel states was the limiting factor in a dose- gave the slides prepared by Marcus E with different affinities, and that drug escalation study. Other side-effects Risner (GlaxoSmithKline, USA), who binding alters the transition rates included nausea, vomiting, agitation, was unable to attend the meeting, that between different states. confusion and drowsiness (Dorman et described lamotrigine as a treatment for The study by Xie and al., 1996). It is unlikely that these epilepsy and other disorders. Garthwaite (1996) showed that the side-effects are due to blockade of Na+ Lamotrigine (Lamictal), a chemically inhibition of Na+ currents by channels since they are not observed novel phenyltriazine, was synthesised Sipatrigine BW619C89 is due to with lamotrigine, which is marketed and developed by Wellcome scientists modulation of channel gating rather for the treatment of epilepsy. The in response to an unmet medical need than an open channel block. A Phase II trial for BW619C89 for the treatment of epilepsy. They selective stabilisation of the inactivated (sipatrigine) was terminated when examined the possibility that antifolate state of the Na+ channel appears Glaxo merged with Wellcome and a compounds had anticonvulsant directly to counter Na+ entry into decision was made to develop the efficacy. Preclinical studies initiated in neurones and thus indirectly decrease NMDA (glycine site) receptor the 1970s demonstrated that one depletion of ATP stores, calcium influx antagonist gavestinel (from Glaxo), antifolate (lamotrigine) was, indeed, a and excessive release of glutamate and which showed no efficacy in a potent anticonvulsant in several animal aspartate. State-dependent modulation randomised, double-blind, placebo- models. Subsequent studies revealed of Na+ channels thus provides a controlled trial (Lees et al., 2000). no teratogenic, carcinogenic or mechanism for selective drug action, Sipatrigine has undergone mutagenic liability, a wide therapeutic since only excessive activation is extensive preclinical studies leading to index and a favourable pharmacokinetic blocked, leaving normal synaptic a series of clinical safety studies in profile. Lamotrigine is thought to act transmission unimpaired. Sipatrigine, both healthy volunteers and stroke primarily via a use-dependent blockade together with a number of other Na+ patients. An efficacy study is planned (continued on page 7) page 7

+ (continued from page 6) William A Catterall Table 2 Na channel blockers displaying neuroprotective efficacy in models of cerebral ischaemia and traumatic brain injury of voltage-sensitive sodium channels to (University of stabilise the neuronal membrane. It Washington, USA) Evidence of efficacy in disease models diminishes the over-excitation of described elegant Compound Focal ischaemia Global ischaemia Traumatic brain injury neurons displaying epileptiform activity studies relating Sipatrigine Yes Yes Yes and has no effect on normal neuronal structure to function BW1003C87 Yes Yes Yes activity. In the clinic, lamotrigine has within sodium Riluzole Yes Yes Yes proven to be a broad-spectrum anti- channels. The epileptic drug as an add-on therapy for channels are adult and paediatric partial seizures and composed of a large α-subunit NMR spectroscopy and forms the basis also as an add-on therapy for the together with one or two β-subunits. for a mechanistic interpretation of site- generalised seizures of Lennox-Gastaut The α-subunit is the pore-forming directed mutagenesis studies of the syndrome. It is also effective as a subunit. β-subunits are single inactivation process. The inactivation monotherapy, given either to patients membrane-spanning glycoproteins gate folds into a receptor region formed with newly diagnosed partial or containing immuno-globulin-like folds by the IIIS4-S5 loop, the IVS4-S5 loop, generalised seizures, or to patients in their extracellular domains. They and the intracellular end of the IVS6 converted from other anti-epileptic segment. interact with the α-subunit through drugs. Lamotrigine’s safety profile is Local anaesthetics and related their extracellular domains and generally unremarkable, and most drugs block the pore of sodium modulate channel expression and adverse events reported by patients are channels by binding to a receptor site gating. The immunoglobulin-like mild or moderate in intensity, are seen formed by amino acid residues in folds have the structures of cell- in the first 6–8 weeks of therapy and transmembrane segment S6 in domains adhesion molecules and interact with resolve without the need to discontinue III and IV. Site-directed mutations of extracellular proteins like tenascin and taking the drug. The most concerning critical amino acids at similar positions cell-adhesion molecules like adverse event is a skin rash, which is α in these segments greatly reduce the generally simple morbilliform in neurofascin. The -subunits are affinity for local anesthetic block and presentation, although more serious organised into four homologous specifically disrupt high-affinity cutaneous reactions have also occurred; domains (I–IV), each of which contain binding to the inactivated state. Many α following the recommended dosing six transmembrane -helices (S1–S6). different structural classes of sodium guidelines minimises this risk. The S4 segments contain channel blockers, including Lamotrigine is currently positively charged residues, which anticonvulsant, antiarrhythmic, and available for the treatment of epilepsy serve as voltage sensors for channel neuro-protective drugs, interact with in over 90 countries, having first activation and move outward under the this site in the pore. received approval in Ireland in 1990 influence of the electric field to initiate In contrast, peptide scorpion and in the UK in 1991, and has been activation. The S5 and S6 segments toxins which alter gating of sodium administered to well over three million and the short membrane-associated channels bind to the extracellular ends patients worldwide. As a consequence segments between them (SS1/SS2) of S4 segments and trap them in either of its widespread use, it has been form the pore. The fast inactivation of an activated or non-activated state. The observed that lamotrigine appears to the open sodium channel is mediated toxins from the α-scorpion trap the improve mood, which has been by closure of a hinged-lid-like IVS4 segment in its inward position inactivation gate formed by the substantiated and extended in a number and slow or prevent inactivation; β- intracellular loop between domains III of clinical trials where has been scorpion toxins trap the IIS4 segment in and IV. The hydrophobic motif IFM demonstrated in patients with bipolar its outward position and greatly within this loop serves as the disorder (Calabrese et al., 2000). This enhance activation. Voltage-sensor inactivation particle. This motif work is being taken forward by trapping may be a general mechanism moves from a cytoplasmic location GlaxoSmithKline. Lamotrigine has of action of peptide toxins which affect into the channel structure during also been shown to have efficacy in a ion-channel gating. These toxin inactivation and becomes inaccessible number of different types of human receptors may provide novel sites for to chemical modification. The three- neuropathic pain (Eisenberg et al., targeting new sodium channel dimensional structure of the core of 2001). modulating drugs. the inactivation gate, including the Catterall presented his sliding IFM motif, has been determined by Relating structure to function helix model of O voltage-dependent HO O gating and showed + H N 2 N H how peptide OH N N O O H scorpion toxins N OH H H N N O alter the gating of HO 2 H NH OH O 2 sodium channels. Toxins from the Tetrodotoxin Procaine Phenytoin Carbemazepine (continued on page 8) Figure 3 Miscellaneous sodium-channel blockers page 8

(continued from page 7) pain permissive interactions that facilitate β-scorpion shift activation negatively John N Wood (University College high-level sodium-channel expression by binding to the S3-S4 loop in domain London) described the role of sodium may be a route to targeting sodium II, whereas α-scorpion toxins (and sea- channels in the mechanisms channel subtypes and disruping anemone toxins) slow coupling of underlying pain. Electro- nociceptive processing. The TTX’s activation to inactivation by binding to physiological studies of dorsal root channel Nav1.3 is present in sensory the S3-S4 loop in domain IV. In the ganglion (DRG) neurons, and the neurones during embryonic former case, the channel must be results of polymerase chain reaction development, but is subsequently activated for the toxin to have effect, (PCR), Northern blot and in-situ down-regulated. It is selectively up- and in the latter case, prolonged hybridisation analyses have regulated in DRG neurons in a variety demonstrated the molecular diversity of models of neuropathic pain. The depolarisation drives the toxin off its + receptor site. Other polypeptide toxins of Na channels that operate in sensory expression of Nav1.3 correlates well α may alter voltage-dependent gating by neurons. Several subtypes of - with the appearance of ectopic action binding tin to the S3-S4 loops of ion subunit have been detected in DRG potentials and allodynia in animal channels, for example hanatoxin neurons and transcripts encoding all models of neuropathic damage, + binding to K channels and the binding three β-subunits are also present. One suggesting that Nav1.3 selective α blockers may be useful for the of both grammotoxin and Agatoxin -subunit, Nav1.8, is selectively IVA to Ca2+ channels. This suggests expressed in C-fibre and A-fibre treatment of neuropathic pain. that voltage- sensor trapping may be a associated sensory neurons that are However, over-expression studies using general mechanism of action of peptide predominantly involved in damage Nav1.3 in normal animals have yet to toxins. The molecular sensing. The production of null be carried out to confirm a causative determinants of lamotrigine binding to mutant mice provides useful role of Nav1.3 in neuropathic pain inactivated sodium channels have information on the specialised syndromes. established that the amino acids IVS6 functions of particular sodium Taken together, the evidence supports a selective and significant role F1764A, IVS6 Y1771A and IIIS6 channels. Nav1.8 null mutant mice are L1465A are critical. The molecular normal apart from deficits in for various sodium channel isoforms in basis for similar drugs having different inflammatory pain (induced by CFA different pain states. The development therapeutic actions (anticonvulsant, or NGF) and noxious mechano- of isoform-specific channel blockers antiarrhythmic and neuro-protective) sensation. Neuropathic pain develops will prove invaluable in determining the role of sodium channel isoforms in pain remains to be elucidated. By contrast, normally in the absence of Nav1.8. it was pointed out that BIII 890 CL, the These data support the idea that pathways, and are likely to provide a fresh approach for the development of Boehringer Ingelheim compound that is selective blockers of Nav1.8 may be in clinical trials for stroke (see Figure 2; useful for treating acute or new analgesic drugs. Carter et al., 2000), binds to the same inflammatory pain. However, at the site as lamotrigine, but with a 30-fold moment, there are no subtype selective Sodium channels in greater affinity. Compounds that are blockers to explore this potentially hypertension and arrhythmia potent sodium channel blockers are attractive approach to pain treatment. Nick Carter (St George’s Hospital, likely to have a reduced probability of An alternative approach to blocking London) related sodium channel interacting with other receptors and channel function is to manipulate structure to function by describing how channels and can therefore be expected channel expression. Using yeast two- specific mutations in sodium channels to possess a better side-effect profile. hybrid cloning a number of interacting cause distinct and deleterious symptoms. He specifically described proteins that bind Nav1.8 have been The role of sodium channels in identified. Disrupting essential or sodium channelopathies relating to hypertension and arrhythmia. Essential hypertension is Cl Cl caused by a number Cl Cl Cl of factors including genetics. Both single gene and Cl Cl Cl polygenic NH contribution can 2 H N alter the clinical H 2N 2 F N phenotype and the N N majority of genes N N N involved appear to affect renal physiology. Liddle NH2 N H N H 2 2 syndrome is a rare BW1003C87 (GW273293) BW4030W92 GW 273293 monogenic Neuro-protective Analgesic Analgesic hypertension Figure 4 Phenylpyrmidines with different efficacies (continued on page 9) page 9

(continued from page 8) seizures. The latter disorder is caused between anticonvulsant and analgesic β phenotype relating to mutations in the by mutations on the 1-subunit. activity (carrageenan paw), which epithelial sodium channel gene ENaC. supports the contention that different Liddle syndrome is usually Prospects for next-generation blockers have different efficacies. The caused by truncation mutations in the sodium channel blockers foundation establishing structure– β-subunit gene producing increased Dr Brian Cox (GlaxoSmithKline) activity relationships for sodium renal channel activity, sodium described the structure–activity channel blockers has now been laid absorption, volume expansion and relationships of a series of sodium (Clare et al., 2000; Anger et al., 2001). increased blood pressure. A mis-sense channel blockers. He pointed out that Further elaboration of structure–activity mutation in the C-terminus, the ‘Liddle neuronal sodium channel blockers relationships will require the cloning region’, has been demonstrated to be a have been used in therapy for many and stable expression of the various contributing factor in common years, long before a connection with subtypes of channel, together with the polygenic multifactorial high blood the modulation of sodium channels development of high-throughput pressure. The polymorphism involved was made or indeed the specific assays. (T594M) is frequent in African and existence of sodium channels was Afro-Caribbean black people but is not known. New assays for sodium channel found in Caucasians. Thus rare and The origins of all the neuronal activity frequent inherited channelopathies can sodium channel blockers lie in two The development of new and high- contribute to hypertension. ENaC is areas: the naturally occurring and throughput assays to assess sodium inhibited by Amiloride and thus complex toxins such as tetrodotoxin channel activity was described by Dr patients with Liddle syndrome may be (TTX) and the synthetic molecules Jesus E Gonzalez (Aurora Biosciences more effectively treated with this such as the local anaesthetic procaine, Corp, San Diego, USA). The assays compound, although routine diuretics the anticonvulsant phenytoin and the use voltage-sensitive fluorescence have also proved effective. The antipsychotic and anticonvulsant drug resonance energy transfer (FRET) molecular changes in ENaC, which carbamazapine (see Figure 3). TTX probes coupled with a Voltage/Ion TM cause increased channel activity, are derives from the puffer fish Probe Reader (VIPR II ), a custom dominant negative. Other ENaC (conveniently all its sodium channels fluorescence plate reader. There are mutations will be described which are resistant to TTX) and binds to the two probes. The first is oxonol, a cause loss of channel function and outer pore of the majority of neuronal highly fluorescent, negatively charged, hence sodium loss with concomitant sodium channels. Both procaine and hydrophobic ion that is sensitive to low blood pressure. phenytoin are synthetic compounds changes in membrane potential. In Sudden cardiac death from and began therapeutic use in 1902 and response to these changes, it can rapidly arrhythmia can be caused by inherited 1937, respectively, but it was not until redistribute between two binding sites channelopathies such as long QT 1959 in the case of procaine and 1983 on opposite sides of the plasma syndrome. This is a dominantly for phenytoin that their action on membrane. The second fluorescent inherited condition resulting from sodium channels was elucidated. molecule is coumarin lipid, which mutations in one of several ion- Since the discovery of the first sodium binds specifically to one face of the channel-coding genes important in channel blockers there has been plasma membrane and functions as a mediating the cardiac action potential. enormous interest in the field. The FRET donor to the voltage-sensing One gene locus associated with this search for better local anaesthetics and oxonol acceptor molecule. When the phenotype is Nav1.5 coding for a anticonvulsants has continued, as well oxonol moves to the intracellular sodium channel protein which, when as that of compounds finding new plasma membrane binding site upon altered by mutations in key regions of uses for entirely new indications, for depolarisation, FRET is decreased and the channel, closes more slowly and example as antiarrhythmics, for stroke results in an increase in the donor causes the QT interval to be lengthened. or bipolar disorder. fluorescence and a decrease in oxonol This phenomenon predisposes to life- Lamotrigine was first emission. This approach enables threatening arrhythmias. It is clear that synthesised and developed in response sodium channel function to happen in a any new sodium channel blocker should to an unmet medical need for the second or sub-second time-frame. be devoid of arrhythmia-inducing treatment of epilepsy, but has become They have screened 125,000 activity, so knowledge of the extent of an important lead for the discovery of compounds against both the type IIA- + interaction at this channel subtype will further generations of compounds such like Na channel endogenously be important in order to avoid as the stroke agent sipatrigine, the expressed in Chinese hamster ovary + unwanted side-effects. selective anticonvulsant GW273293 (CHO) cells and the human cardiac Na The location of mutations that and the selective analgesic GW286103 channel (hH1a) heterologously impair sodium channel activation and (see Figure 4). There were good expressed in HEK293 cells. A large cause inherited diseases of correlations between 1) TTX-resistant group of compounds were active at + hyperexcitablity were described by currents in DRG neurons (in vitro) and both Na channel types and a few Professor Catterall. In addition to analgesia (in vivo); and 2) inhibition at compounds showed subtype selectivity. causing long QT syndrome, such cloned Type IIA sodium channels and The functional FRET assays have mutations have also been found to in vivo anticonvulsant activity. significant advantages for medicinal cause periodic paralysis and febrile There was no relationship (continued on page 14) page 10

From left to right, the SMR Award recipients, David Haigh, Richard Hindley, Michael Cawthorne, Stephen Smith and Barrie Cantello

on the idea of targeting the insulin target profile criteria: BRL 48482, (continued from page 3) resistance, hopefully with small BRL 48552 and BRL 49653. project team, each received a framed molecules. The goal was to identify In order to determine the final certificate in recognition of their compounds that would provide candidate choice, it was necessary to achievement, presented by the durable glucose control and also develop a selectivity screen that chairman of the SMR, Dr David reduce the cardiovascular-associated monitored haemodilutional effects. Cavalla. The monetary prize disease problems known to Any compound of interest would need accompanying the award was donated accompany diabetes. to have no lowering of haematocrit in to the charity, Diabetes UK, at the At the time virtually nothing rodents at multiple doses of the anti- unanimous request of the award was known about the molecular diabetic dose. BRL 49653 was shown winners. Dr Stephen Smith (now of mechanisms of the insulin action and to be 100-fold selective and was chosen GlaxoSmithKline) delivered the award the project team had to rely on a catch- for development in 1992. The company lecture. The prevalence and existing all mouse model of insulin-resistant was now SmithKline Beecham. treatments for diabetes provide an type 2 diabetes. Thus, the target Clinical efficacy of rosiglitazone was important background to this research profile for any compound of interest established in 1995. During the early effort. Type 2 diabetes is a chronic was defined as follows: orally potent 1990s many groups had been looking disorder of glucose metabolism (1mg/kg), active in a mouse model for the identity of the molecular target afflicting 5–10% of the adult (ob/ob mouse), active at three dose of the TZDs. TZDs were known to population of Western societies and is levels in eight-day repeat dose studies, promote the differentiation of fat predicted to rise from >150 million active in dietary admixture, and have precursor cells in tissue culture over worldwide now to 220 million by 2010, efficacy assessed by an oral glucose several days, which suggested a particularly because of China. Diabetes tolerance test with a reduction in the mechanism involving changes in gene management requires a combination of area under the curve of 25%. The lead expression. The peroxisome diet, exercise and drug programmes. compound was ciglitazone, a proliferator-activated receptors The sulphonylureas (SUs) and thiazolidinedione (TZD), which had (PPARs) and ligand-activated nuclear metformin were introduced 20–40 years been derived from the hypolipidaemic receptors were identified but the native ago and do not directly target the drug clofibrate, and which was only a ligands remained unknown at the time. fundamental problem of insulin very weak insulin sensitiser. A PPAR-alpha was shown to be a target resistance. They do not control glucose metabolite was found to be 30-fold for fibrate hypolipidaemic agents and long term and many patients eventually more potent. SAR on the metabolite PPAR-gamma was the target for TZD require insulin. The research for a and the synthesis of over 300 insulin-sensitising anti-diabetic drugs. novel treatment to type 2 diabetes compounds led to the discovery of PPAR-gamma is highly expressed in started in 1984 at Beecham three potential development fat, but less so in skeletal muscle and Laboratories in Surrey and was based compounds all of which fulfilled the (continued on page 11) page 11

(continued from page 10) industry that has thrived since the issue of getting the R&D correct. The liver. PPAR-gamma activation leads 1950s, he asked several fundamental industry has become technology driven recruitment of the retinoic acid nuclear questions. Was the industry running because of genomics. While it has receptor RXR which bind to genes out of steam? What was driving the provided more targets to choose from, containing peroxisome proliferator consolidation of so many companies there is a consequent need to increase response elements (PPREs). Many of (the merger and acquisitions, M&A)? the amount of data and information in these are key gene-encoding proteins sector companies have order to make the correct choices of controlling lipid and glucose an important part to play in which to take forward. Transforming metabolism. Extensive clinical studies supplementing large pharmas’ own this into new products is taking showed that Avandia maintains efficacy research activities, but with the considerable time and effort. Big over the treatment periods. This is also industry’s need to reinvent product pharma is good at the ‘D’ part: maintained in the presence of sulphonyl portfolios every 15 years or so in order marketing, distribution, dealing with ureas and metformin. Avandia was to offset sale losses arising from patent regulatory authorities, but the huge launched in the US in 1999 and the UK expiry, will the biotech companies be bureaucracies they have created may in 2000 and has been used in more than able to deliver on time? have stifled the creative ‘R’ 2.5 million patients worldwide. Overall, the rate of output of environment preventing them Successful drug discovery is a new chemical entities (NCEs) is no innovating at the appropriate rate. significant achievement for those greater now than it was before the There appears to be no doubt that involved and is really quite a rarity mergers. The generic industry is likely smaller companies with less given the investment that is poured into to be a beneficiary. With the need to bureaucracy offer a creative R&D. Currently, there is a great charge more for medicines to recoup opportunity, many of these are set up on demand for an increase in new and large investment costs and cover the the back of academic discovery. better medicines, which puts enormous shortfall in NCEs, this will encourage Something more flexible than M&A is pressure on the industry to deliver. Dr to an even greater extent the use of needed. One solution may be for large Philip Brown (executive chairman, low-priced generics and be a safety pharma to create smaller cohorts from PJP Publications Ltd), who founded valve on pricing. M&As offer the its research base to stimulate more SCRIP World Pharmaceutical News, promise that bigger is better but appear creative environments. gave his perspective on the state of the no more than a financial survival Regrettably, due to illness and and provided strategy. It is clear that the large travel restrictions after 11 September, an assessment of its future. For an pharma are the drivers but it will be an the meeting was deprived of two talks.

SMR chairman, Dr David Cavalla, passes the cheque for the SMR Award to a representative of the British Diabetes Founda- tion at the request of Professor Michael Cawthorne (centre) and the rest of the project team page 12

Medicinal Chemistry at King’s College design, particularly aspects which have a strong lead from molecular London modelling. The by R.C. Hider group is well-funded by MRC, EPSRC, NIH, BBSRC, FSA, BTG, EU, The Department of Pharmacy at King’s received considerable income from charities and industry. College London has had a long history successful SRIF bids. In addition, the Synthetic chemistry is a major originating at Chelsea College in the Drug Control Centre, which grew out strength in the department, and includes late 1890s. Pharmacy gradually of the Pharmacy Department and is three principal areas: peptides, became an increasingly important directed by Professor David Cowan, is chelation chemistry and natural subject at Chelsea College, and in the located on the fourth floor of the products. Dr Sukhi Bansal works 1950s and 1960s the staff, under the Franklin-Wilkins building. The centre almost entirely with peptide chemistry leadership of Professor Arnold Beckett, has in recent years played an and has produced an extremely useful made major contributions in the fields increasingly important role both in the fluorescent probe which has potential of drug stereochemistry, analytical teaching and research activities of the for labelling a wide range of science and medicinal chemistry. school. biomolecules and has been used in the Pharmacy at Chelsea College merged Pharmacy, in common with department for the investigation of with King’s College in 1985, along other UK departments, teaches a four- peptide absorption across lung and with several other health sciences; for year MPharm degree, but unlike most intestinal tissue. Sukhi has also instance, Nutrition from Queen other departments also runs three MSc developed a new method for labelling Elizabeth College, and Nursing from a courses, each of which has been taught peptides with 18F (T½=110 minutes) number of London medical schools and for over 30 years: Biopharmacy, which is used for positron emission Chelsea College. Pharmaceutical Analysis and tomography. By using solid support Pharmaceutical Technology. These synthesis, peptides can be produced Health science focus three degrees form a modular within 20 minutes, and the method has Since that date, health sciences have framework with the Forensic Science found immediate clinical application been a strong component of the college. MSc degree. The school has a strong here at King’s College London. Dr In 1998 we were fortunate to move to tradition of postgraduate teaching, not Bansal’s group concentrates on solid- the completely refurbished Franklin- only in pharmacy but also in biological phase peptide synthesis, and has Wilkins building at the Waterloo site. and analytical science. developed a number of new synthetic This magnificent building accom- The research activities in procedures, including one for on- modates the entire School of Health and Pharmacy are distributed between five column synthesis of cyclic Life Sciences. It is an enormous research groups: Natural Products and oligopeptides. structure with six floors, each with a Medicinal Chemistry, Biochemical floor area of over 4,000 square metres. Toxicology and Drug Disposition, Hider’s synthetic group Pharmacy is located on the fifth floor, Drug Delivery and Absorption, The synthetic group led by Bob Hider where we undertake the majority of Molecular and Pharmacy provides the international lead in the teaching and research. Thus, for the Practice. The standard of research in design of orally-active iron chelators. first time in our long history, we are the department has increased Deferiprone, which was designed by working in purpose-designed facilities, dramatically over the last decade. Hider in the mid-1980s, is now and in close association with a large Thus, whereas our research rating in extensively used as a mainline part of the college. Waterloo is the 1989 was 2, it increased to 4 in 1992, treatment for thalassaemia in many centre of the major King’s College was maintained at 4 in 1996, and in the parts of Europe, Iran and India. sites. The Strand, where the physical recent exercise of 2001 was rated 5. Second-generation hydroxy- sciences are taught, is only separated by This gradual improvement has been pyridones, also designed by Hider’s Waterloo Bridge, and St Thomas’ and achieved by the appointment of high- group, are in preclinical development Guy’s, to the west and east of Waterloo, calibre staff who are interested in both by Apotex (Canada) for use against iron are both 10 to 15 minutes’ walk away. research and teaching. overload associated with thalassaemia Thus, not only does Pharmacy have The medicinal chemists in the and sickle-cell anaemia. These close links with Life Sciences and department make a major contribution compounds are the most powerful Chemistry, but also with the Medical to the activities of the four bidentate iron chelators known, and are School, which is associated with three pharmaceutical science groups listed currently under investigation for a major teaching hospitals: St Thomas’, above. The chemists are involved with range of additional clinical Guy’s and King’s College. synthesising lead compounds which applications. One recent example is Within the Franklin-Wilkins have emerged from natural product associated with the successful building there are several research studies, with the Drug Delivery group application of phototherapy to surface centres: the Electron Microscopy in designing new formulations, with tumours, for instance, those located on Centre, the Mass-spectrometry Centre, the analysts in designing new column the skin, bladder and oesophagus. The and the Genomics Centre. These are all matrices for separation purposes, and technique is based on the manipulation co-ordinated by the School of Health with the Molecular Biophysics group of local laser-generated oxygen radicals and Life Sciences and have recently over matters relating to molecular (continued on page 13) page 13

(continued from page 12) but is also highly innovative in the companies including GSK and via protoporphyrin IX. Some chelators development of novel molecular- AstraZeneca. inhibit ferrochelatase, thereby enhancing modelling software. The software tools Analytical science is a key the concentration of protoporphyrin IX most recently developed include activity in the department and overlaps and so sensitising the tumour. This programmes for modelling the structure with many of the medicinal chemistry concept is under development by several of surfactant aggregates, for making interests. Drs Giuliano Siligardi and start-up companies at the present time. sequence-based predictions of protein Alex Drake run a state-of-the-art The group has also developed a function, and for rapid quantification of spectroscopy lab with particular method for the measurement of non- molecular topographical similarity and expertise in the application of circular transferrin-bound iron, a toxic species complementarity. Specific success dichroism to biological molecules and present in the plasma in many disease stories in terms of molecular structure drug-macromolecule interactions. Drs states, including haemochromatosis. prediction include the sequence-based Melissa Hanna-Brown and Andrew Hutt This analytical procedure is now used prediction of the structure of the peptide are involved in the development of new throughout Europe, North America and hormone endothelin and the Dcytb ferric analytical techniques based on HPLC South-east Asia. As a result of these reductase. and CE for the rapid determination of advances related to iron chelation and Molecular modelling also plays a drug partition characteristics and drug– iron , Hider was able to critical role in an ongoing programme lipid interactions. An additional interest attract funding from the MRC to form the aimed at developing novel non-ionic and is in the analysis and preparative Iron Metabolism Group, which now has zwitterionic surfactants for use as drug- resolution of chiral compounds for both co-operative status with the MRC. This delivery systems. This work is a joint chiroptical characterisation and group includes biochemists, nutritionists, venture between Drs David Barlow and pharmacological evaluation. The molecular biologists, clinicians and Jayne Lawrence and is one of only two contributions of this group were recently medicinal chemists, and fits well into the such programmes in the UK. The com- recognised internationally by the new interdisciplinary strategy of the bination of molecular modelling with awarding of the Desty Prize for School of Health and Life Sciences. sophisticated analytical tools such as Chromatographic Science to Melissa, neutron scattering has enabled a detailed and the Jan Weber Medal to Andrew — Interdisciplinary projects picture of the molecular architecture of a both in 2000. There are many joint projects between range of surfactant systems (including The major task for medicinal the pharmacognisists and medicinal vesicles and micelles), to be constructed chemists is to design new molecules with chemists at King’s College. One which both in the absence and presence of a therapeutic potential. The chemists in typifies this close interaction, is the drug. This knowledge has been essential the Department of Pharmacy at King’s development of a new treatment for both in the design of novel surfactants have an excellent opportunity to achieve vitiligo, a project led by Dr Amala with built-in physico-chemical this, being situated in a single building Raman and currently funded by BTG. Dr properties, as well as facilitating our together with biochemists, Raman’s research group has established understanding of the behaviour of immunologists and molecular biologists, that piperine is associated with pigment existing surfactant drug delivery and also in close contact with members cell stimulation in vitro. The project systems. The programme is well funded of the Medical School — with whom we involves the design, synthesis and in by a number of pharmaceutical plan to increase our interaction and vitro and in vivo biological assessment of a range of synthetic analogues; a number of active analogues have been identified. Underpinning many of the molecular design projects in the department, Dr David Barlow leads an active group, equipped with state-of the-art, high performance silicon graphics and Compaq alpha workstations. Dr Barlow’s group is not only occupied in applying established molecular graphics and QSAR techniques to problems, page 14

(continued from page 9) likely that more such channelopathies Notes chemistry support, rapid prioritisation will be discovered in the future. The of candidate blockers and exploring diversity and dynamic nature of sodium Future SMR meetings (contact drug/channel interactions. This channel expression introduce a high secretariat for more infor- comparative screening approach should degree of complexity into the nervous be applicable to other members of the system. This not only presents a great mation, the e-mail address is Na+ channel family. challenge for neuroscience, but it also secretariat@ socmr.org): The discovery of the first provides a golden opportunity for generation of sodium channel blockers future work in drug discovery, 7 March 2002. Orphan Receptors was made with little dependence on particularly with the use of recombinant (Novartis, Horsham). recombinant channels. It was sodium channels and new high- established that such compounds block throughput technologies to assess 27 June 2002. , over-activated sodium channels, while sodium channel function. Pharmacokinetics and Drug Discovery permitting normal currents of sodium (National Heart and Lung Institute, ions. This has provided a basis to References London). develop such sodium channel blockers Anger, A, Madge, DJ, Mulla, M and for the treatment of CNS disorders such Riddall, DJ (2001) J. Med. Chem. 19 September 2002. Proteomics: joint as epilepsy, stroke, traumatic brain 44(2): 117–37. meeting with BMCS section of RSC injury and pain. Calabrese, JR et al. (2000) J. Clin. (Scientific Societies’ Lecture Theatre, Psychiatry 61(11): 841–50. London). Conclusion Carter, AJ et al. (2000) Cl. Proc. Natl. Sodium channel blockers may also have Acad. Sci. 97(9): 4944–9. NEW MEMBERS utility for other types of illness, such as Clare, JJ et al. (2000) Drug Discovery Amersham Pharmacia Biotech: Dr AR bipolar disorder. The ability of sodium Today 5: 506–20. Ali, Miss S Davies; AstraZeneca: Dr W channel blocking drugs to attenuate Eisenberg, Y. et al. (2001) Neurology McCoull, Dr C Reilly; BioFocus: Dr J abnormal activity of sodium channels 57: 505–9. Duffy Dr C Lauret; British Biotech: Dr without affecting normal synaptic Goldin, AL et al. (2000) Neuron 28(2): SP East; Cardiff University: Dr KT transmission probably underlies their 365–8. Wann; CeNeS: Dr R Croxen, Dr AP good tolerability. With the discovery of Keating, MT and Sanguinetti, M.C. Southan; De Montfort University: Dr nearly a dozen genes encoding different AH Hainsworth; University of Dundee: sodium channels, it is clear that the next Former SMR Award Winner, Dr X Mwimbi; GlaxoSmithKline: Dr M generation of sodium channel blockers Professor Stenlake, Receives Ahmed, Mr Y-KC Chung, Dr G Cooper, will have to be made with knowledge of Further Accolade Dr DJ Davies, Dr M Davy, Mr AT subtype selectivity. Establishing how Doran, Mr Neil Garton, Dr MD Hall, Dr the different channels relate to different We have been informed that one of the RE Kelsell, Mr DJ Mitchell, Dr SF disease states is clearly an important first recipients of the SMR Award for Moss, Mr TJ Smith, Dr S Westway; challenge. Progress has begun with Drug Discovery, Professor John Stenlake, Innovata Biomed: Dr M Parry-Billings; studies with null mutants for different who was recognised in 1987 for his Medivir UK: Dr C Clissold, Dr V sodium channels, together with contribution to the discovery of Morisson; Millennium Pharmaceuticals: evidence of maladaptive changes in atracurium, has been further Dr LJ Payne; Nature Publishing Group: sodium channel gene expression in acknowledged with the award of the Dr AL Smith; No affiliation: Mr S neurons in certain pathological states. Hanbury Medal for 2001 for original Maccormick; Odyssey Pharmaceuticals: These studies will be greatly research in the natural history and Dr MJ Powell; Organon Laboratories: complemented by blockers with clear chemistry of drugs. Dr RE Armer, Ms KI Buchanan, Dr R subunit selectivity. Whether such The medal, jointly awarded by the Gilfillan, Dr AJR Mason; OSI compounds are feasible remains to be Royal Pharmaceutical Society of Great Pharmaceuticals: Dr SC Hirst Dr M seen. It is possible that compounds with Britain and the Linnean Society, Fyfe; Oxagen: Dr N Lench; Pfizer: Dr different efficacy profiles bind to the acknowledged the invention and clinical GN Maw; Pudue Pharma: Dr P same site within transmembrane merits of the novel skeletal muscle Gharagozloo; St George’s Hospital segments IIIS6 and IVS6 of inactivated relaxant atracurium besylate for use in Medical School: Miss KT Gormley; sodium channels. The continued surgery and intensive care. The : Ms NH Allen, Ms K careful elucidation of structure–function Department of Pharmaceutical Sciences at Benwell, Dr N Carey, Mr J Horswill, Dr relationships within the sodium the University of Strathclyde and the LJS Knutsen, Mr D Revell; Xenova: Dr channel will also facilitate future drug Wellcome Foundation also shared a F Wilson. discovery. Queen’s award for technological The relationship between innovation in 1986 for atracurium. NEWSLETTER PRODUCTION structure and function is also helped by We are very pleased for Professor Edited and produced by Corwen the discovery that mutations in specific Stenlake that his achievements, which we McCutcheon. Please send contributions isoforms of sodium channel cause a recognised early on, continue to receive to the SMR Secretariat, preferably by variety of diseases, including paralysis, recognition from the wider public.• e-mail at [email protected]. • long QT syndrome and epilepsy. It is