Combinatorial Chemistry Online Volume 13, Issue 5, May 2011 N.K

Combinatorial Chemistry - An Online Journal 13 (2011) 17–19

Contents lists available at ScienceDirect

Combinatorial Chemistry - An Online Journal

journal homepage: www.elsevier.com/locate/comche

Combinatorial Chemistry Online Volume 13, Issue 5, May 2011 N.K. Terrett

Ensemble Therapeutics Corp., Cambridge, MA 02139, USA

1. Current literature highlights Parallel synthesis was undertaken using test tube reaction blocks or stir-plate mounted racks of reaction vials. It was found 1.1. A solution phase library of allosteric mGluR4 modulators that any modification of the central homopiperazine core was not tolerated by mGlu4. Conversion to the piperazine, oxohomo- Parkinson’s disease (PD) remains a significant neurodegenera- piperazine, oxopiperazine or to bridged [3.3.0] scaffolds resulted tive disease that is poorly treated with existing therapies. The in a loss of activity. The next phase of investigation maintained disease is caused by the degeneration of dopaminergic neurons the right-side of the molecule and varied the amide aromatic ring in the substantia nigra of the brain leading to movement disorders with various heterocycles and alkyl groups. Modification resulted which can be distressing and debilitating. The metabotropic gluta- in compounds with weak binding although good efficacy (equiva- mate receptor 4 (mGlu4) is expressed on a key synapse in basal lent to the known mGlu4R PAM, PHCCC) was observed. Such flat ganglia circuitry, and studies have demonstrated that mGlu4 acti- SAR is frequently characteristic of allosteric binders. vation results in anti-Parkinsonian effects in rodent models of PD. Having established the role of this receptor, several groups have MeO investigated the effect of compounds that activate the receptor. In particular, positive allosteric modulators (PAMs) offer potential in treating PD, as they increase the potency of glutamate, the O endogenous neurotransmitter for the mGlu4 receptor. A recent report describes the use of high-throughput screening (HTS) and N S a solution-phase parallel synthesis approach to identify novel MeO H NNS positive allosteric modulators of mGlu4.1 O O A small molecule library was screened at 10 lM to identify 2 compounds that had agonist, antagonist, or allosteric modulator activity in CHO cells that express human mGlu4 receptors. Com- pounds were added to cells prior to the addition of a stimulatory concentration of glutamate, and from this study, a novel scaffold, The last part of the molecule that was modified was the right- represented by compound 1 was found to be a positive allosteric hand sulphonamide moiety, and the parallel synthesis of 38 differ- modulator of the mGlu4 receptor (EC50 = 7.5 lM). The presence ent sulphonamides covered a range of phenyl, benzyl, alkyl, and of a nonplanar homopiperazine scaffold containing a basic nitrogen heteroaryl groups. Several of these compounds showed good po- provided an excellent opportunity to explore SAR around this HTS tency and efficacy (e.g. compound 2;EC50 = 1.8 lM, efficacy rela- lead using a parallel solution-phase synthetic approach. tive to PHCCC = 52.9%), and were advanced to pharmacokinetic studies. Although this work disclosed a novel chemotype that acts MeO as a PAM of the mGlu4 receptor, further progression of the com- OMe pounds was limited as the compounds had inadequate pharmacokinetic properties such as poor metabolic stability and CYP 2C9 and O CYP 2D6 inhibition.

N MeO H NN S 2. A summary of the papers in this month’s issue O O 1 2.1. Solid-phase synthesis

A basic alumina-supported solvent-free one-pot synthesis of pyridine-fused polycyclic diazepaniums has been achieved using E-mail: [email protected] microwave irradiation. The process was successfully extended to doi:10.1016/j.comche.2011.04.001 18 N.K. Terrett / Combinatorial Chemistry - An Online Journal 13 (2011) 17–19 the synthesis of pyridine-fused bicyclic imidazolidiniums and tet- and also modified amino acids can be included. Selected library rahydro-pyrimidiniums and also of tri- and tetracyclic diaza-het- peptides bound to HLA were isolated by size exclusion chromatog- erocycle-fused quinoliniums. The dual characteristic of basic raphy and sequenced by tandem mass spectrometry online cou- alumina, a solid support as well as a base, was successfully em- pled to liquid chromatography. This novel method, is limited ployed, and the method emerged to be an effective route in terms only by library complexity and sensitivity of mass spectrometry, of yield, reaction time, and ease of purification.2 and allows the analysis of several thousand synthetic sequences Miyaura borylation and Suzuki–Miyaura cross-coupling reac- concomitantly in a simple water soluble format.8 tions have been combined to set up an efficient strategy for the The use of very highly substituted resin has been avoided for solid phase synthesis of biaryl cyclic peptides. The Miyaura boryla- peptide synthesis due to the aggravation of chain–chain interaction was the key step in obtaining the linear peptidyl resin precur- tions within beads. A combined solvation-peptide synthesis ap- sor containing both the boronate and the halogenated derivative of proach has been developed to address this problem, taking as an aromatic amino acid. The Suzuki–Miyaura macrocyclisation was models, several peptide-resins and with peptide contents increas- performed under microwave irradiation leading to biaryl cyclic ing up to near 85%.9 peptides of different ring sizes.3 2.6. Library applications 2.2. Solution-phase synthesis Based on a hit cluster of compounds inhibiting interleukin-2 0 Pd(OAc)2/1,1 -bis(diphenylphosphino)ferrocene as an efficient, inducible T-cell kinase (ITK) in the submicromolar range, a series highly active catalyst for the allylation of amines, alcohols and car- of ITK inhibitor libraries have been synthesised. Through iterative boxylic acids with 1-phenyl-1-propyne has been developed. The design cycles including kinase crystal structure information, indol- effect of various reaction parameters, such as ligand, time, solvent, ylindazole libraries were identified which showed low nanomolar temperature, metal:ligand ratio and catalyst concentration on activity in enzymatic and cellular assays. The potential of these yields of the product have been investigated. The optimised proce- novel lead series was confirmed through in vivo tests in an dure works well under mild operating conditions and permits anti-CD3-IL2 mouse model.10 rapid generation of a library for various allylated products.4 An effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide scaffold has been 2.3. Scaffolds and synthons for combinatorial libraries developed. Compounds were synthesised using a solution phase strategy with overall yields of 50–80%. A series of 15-membered Bicyclic carbohydrate 1,2-lactones have been synthesised in azalide urea and thiourea derivatives were evaluated for in vitro only two steps and high yields by saponification and subsequent antimalarial activity against chloroquine-sensitive (D6), chloro- cyclisation from known malonate addition products to glycals. quine/pyremethamine resistant (W2) and multidrug resistant The gluco-configured lactone serves as an important precursor (TM91C235) strains of Plasmodium falciparum. Most of the synthes- for diversity-oriented syntheses. Thus, stereoselective opening of ised compounds had inhibitory effects against all three strains.11 the lactone ring was realised with various nucleophiles in the A library of 1,4-benzodiazepines has been synthesised and presence of Sc(OTf)3, enabling the introduction of different sub- evaluated against Trypanosoma brucei, a causative parasite of stituents at the anomeric position, to afford a broad variety of Human African trypanosomiasis. Benzodiazepines possessing a 1-functionalised carbohydrates. Carbohydrate 1,2-lactones are P2-transporter motif were found to have MIC values as low as thus attractive precursors for the stereoselective synthesis of di- 0.78 lM.12 verse saccharides.5 Structure based drug design has been used to discover heat The synthesis of multifunctionalised b-ketoesters has been shock protein 90 (HSP90) inhibitors useful in the treatment of can- achieved by using molecular iodine as a catalyst under very mild cer. From the crystal structure of HSP90–ligand complex, a docking conditions. The vinylogous addition of Chan’s diene to carbonyl model was prepared and was validated by an external dataset con- and carbonyl-related compounds (aldehydes, ketones, imines taining known HSP90 inhibitors. This validated model was then and acetals) occurred with high efficiencies and with complete used to virtually screen commercial databases, selected hits of c-selectivity, giving a useful method for the synthesis of interest- which were bought and sent for real biological evaluation. Further, ing libraries of different d-functionalized b-ketoesters.6 as an alternative method, pharmacophores were generated using crystal structure conformations of ligands in HSP90 complexes 2.4. Solid-phase supported reagents and were used for virtual screening. Both cases yielded several hits containing novel scaffolds. These compounds were used as leads A facile one-pot preparation of polystyrene-supported (dichlo- for constructing small molecular libraries to get compounds with roiodo)benzene from polystyrene, iodine, and bleach has been favourable pharmacokinetics and drug like properties.13 developed. This recyclable reagent is useful for efficient chlorina- The design, synthesis and binding affinity for VEGFR-1 receptors tion of organic substrates and selective oxidation of various alco- of a small library of linear and cyclic analogues of the VEGF81–91 hols to the corresponding carbonyl compounds in high yields fragment have been described. Cyclic 11- and 10-mer peptide under mild conditions. The final products are conveniently sepa- derivatives were prepared using parallel solid-phase methods. rated from the polymeric byproduct by simple filtration and iso- The formation of hydrocarbon alkene-bridged cyclic peptides was lated in good purity after evaporation of solvent.7 achieved through optimised ring-closing metathesis reactions from linear derivatives with conveniently located allylGly residues. 2.5. Novel resins, linkers and techniques Binding assays showed that some of these compounds were able to compete with labeled VEGF for interaction with the VEGFR-1 A novel peptide library based method for the identification of receptor, opening the way for using these peptides as the starting HLA class II binding motifs has been reported. The approach is fo- point for biological/pharmacological tools to investigate this cused on water soluble HLA class II molecules and soluble dedi- protein–protein system.14 cated peptide libraries. The peptide libraries were designed so A library of RGD tripeptide analogues cyclised through oxorhe- that the sequence length, the alignment of binding registers, the nium coordination by an NS2/S chelation motif has been synthes- numbers and composition of random positions are controlled, ised. Screening these compounds against integrins aVb3, aIIbb3 N.K. Terrett / Combinatorial Chemistry - An Online Journal 13 (2011) 17–19 19 and aVb5 led to the identification of six oxorhenium complexes Belenguer AM, Friscic T, Day GM, Sanders JKM. Solid-state dynamic combinatorial that bind to integrin aVb3 in the submicromolar range.15 chemistry: reversibility and thermodynamic product selection in covalent mechanosynthesis. Chemical Science 2011;2(4):696–700. New inhibitors of the bacterial transferase MraY have been de- Hinou H, Miyoshi R, Takasu Y, Kai H, Kurogochi M, Arioka S, et al. A strategy scribed. 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