Gold-Mediated Multiple Cysteine Arylation for the Construction of Highly Constrained Bicycle Peptides.

Bicycles are constrained bicyclic peptides formed through reaction of three cysteine residues within a linear sequence with a trivalent, symmetrical small molecule scaffold. Bicycles with high binding affinities to therapeutically important targets can be discovered using screening technologies such as phage display. Increasing the chemical diversity of Bicycles should improve the probability of finding hits to new targets and can be achieved by expanding the toolbox of Bicycle forming chemistries. Gold(III) S-arylation has recently been described as a method for the efficient bioconjugation of cysteine residues under conditions compatible with phage display. Herein, we explore the scope and generality of this methodology for Bicycle construction through the synthesis and evaluation of four novel tris-Gold complexes. These new scaffolds were systematically reacted with a variety of peptide sequences, varying in amino acid loop lengths. All four scaffolds proved to be capable and selective reactive partners for each peptide sequence and afforded the desired Bicycle products in 13-48% isolated yield. This work exemplifies Gold-mediated arylation as a general approach for construction of novel, highly constrained Bicycles.

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.

Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.

Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.

Crystal structures of ASK1-inhibtor complexes provide a platform for structure-based drug design.

ASK1, a member of the MAPK Kinase Kinase family of proteins has been shown to play a key role in cancer, neurodegeneration and cardiovascular diseases and is emerging as a possible drug target. Here we describe a 'replacement-soaking' method that has enabled the high-throughput X-ray structure determination of ASK1/ligand complexes. Comparison of the X-ray structures of five ASK1/ligand complexes from 3 different chemotypes illustrates that the ASK1 ATP binding site is able to accommodate a range of chemical diversity and different binding modes. The replacement-soaking system is also able to tolerate some protein flexibility. This crystal system provides a robust platform for ASK1/ligand structure determination and future structure based drug design.

Biphenyl amides and isosteres as MCH R1 antagonists.

The pursuit of MCH R1 antagonists for the treatment of obesity has become an active area of research for many pharmaceutical companies. The evidence supporting the use of MCH R1 antagonists for the treatment of obesity is ample, and the recent demonstration of MCH R1 antagonists' efficacy in animal models of obesity has served to augment earlier studies involving MCH peptide and transgenic animals. We report herein our search for MCH R1 antagonists from the discovery of a biphenyl amide by high throughput screening, through the optimization of the biphenyl amide to a series of constrained aryl-substituted thienopyrimidinones, and extending the application of the thienopyrimidinone substructure to other series of MCH R1 antagonists. Importantly, these MCH R1 antagonists have demonstrated efficacy in animal models of obesity through once-daily oral administration at low doses.

SAR of biphenyl carboxamide ligands of the human melanin-concentrating hormone receptor 1 (MCH R1): discovery of antagonist SB-568849.

We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.

Discovery of potent and stable conformationally constrained analogues of the MCH R1 antagonist SB-568849.

A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.

Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists.

Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.

Definition of the heterocyclic pharmacophore of bacterial methionyl tRNA synthetase inhibitors: potent antibacterially active non-quinolone analogues.

Potent inhibitors of bacterial methionyl tRNA synthetase (MRS) have previously been reported. Through SAR of the quinolone moiety, the right hand side pharmacophore for MRS inhibition has now been defined as an NH-C-NH functionality in the context of a bicyclic heteroaromatic system. Potent antibacterial fused-pyrimidone and fused-imidazole analogues have been obtained and enantioselective activity demonstrated. Compound 46 demonstrated very good antibacterial activity against panels of antibiotic-resistant staphylococci and enterococci.

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.