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 Drug Discovery 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 Chiroscience Ltd (now SmithKline, New Frontiers Science wherein the protonated form made part of Celltech 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.