ABSTRACT
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.
Subject(s)
Cysteine , Gold , Amino Acid Sequence , Bicycling , Cysteine/chemistry , Gold/chemistry , Peptide Library , Peptides/chemistryABSTRACT
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.
ABSTRACT
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.
Subject(s)
MAP Kinase Kinase Kinase 5/antagonists & inhibitors , MAP Kinase Kinase Kinase 5/chemistry , Staurosporine/chemistry , Binding Sites , Cardiovascular Diseases/drug therapy , Crystallography, X-Ray , Drug Design , Humans , Ligands , MAP Kinase Kinase Kinase 5/genetics , MAP Kinase Kinase Kinase 5/metabolism , Neoplasms/drug therapy , Neurodegenerative Diseases/drug therapy , Sf9 Cells , Signal TransductionSubject(s)
Diabetes Mellitus/drug therapy , Drug Discovery , Glucokinase/metabolism , Janus Kinases/antagonists & inhibitors , Malaria/drug therapy , Receptors, Glucagon/agonists , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Drug Discovery/methods , Glucagon-Like Peptide-1 Receptor , Glucokinase/chemistry , Humans , Plasmodium/drug effectsSubject(s)
Biomedical Research/trends , Drug Industry/trends , Biomedical Research/methods , Drug Design , Drug Industry/methods , Epigenesis, Genetic , Protein Interaction Mapping , Receptor, Muscarinic M2/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Receptors, Prostaglandin/antagonists & inhibitors , TRPV Cation Channels/antagonists & inhibitorsABSTRACT
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.
Subject(s)
Antidepressive Agents, Tricyclic/chemical synthesis , Brain/drug effects , Chemistry, Pharmaceutical/methods , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Animals , Antidepressive Agents, Tricyclic/pharmacology , Blood-Brain Barrier/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/chemistry , Humans , Hydrogen Bonding , Microsomes/drug effects , Models, Chemical , Molecular Conformation , Protein Isoforms , Rats , Serotonin Antagonists/pharmacologyABSTRACT
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.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemistry , Receptors, Pituitary Hormone/antagonists & inhibitors , Receptors, Pituitary Hormone/metabolism , Amides/pharmacokinetics , Animals , Humans , Models, Molecular , Quinolines/chemistry , Receptors, Pituitary Hormone/chemistry , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Amides/chemistry , Amides/pharmacology , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacokinetics , Brain/drug effects , Brain/metabolism , Cattle , Computational Biology , Humans , Ligands , Models, Molecular , Molecular Structure , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/metabolism , Structure-Activity Relationship , Sulfur/chemistryABSTRACT
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.
Subject(s)
Amides/pharmacology , Biphenyl Compounds/pharmacology , Receptors, Somatostatin/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Anilides/chemistry , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Humans , Molecular Structure , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Brain/metabolism , Piperazines/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Administration, Oral , Animals , Biological Availability , Blood-Brain Barrier , Dogs , Molecular Conformation , Permeability , Piperazines/pharmacokinetics , Piperazines/pharmacology , Rats , Serotonin Antagonists/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Methionine-tRNA Ligase/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Enterococcus faecalis/drug effects , Enzyme Inhibitors/pharmacology , Kinetics , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Quinolones , Staphylococcus/drug effects , Structure-Activity RelationshipABSTRACT
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.