ABSTRACT
The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at <1 mg/kg oral doses, and developability properties suitable for progression into preclinical development.
Subject(s)
Carboxylic Acids/chemistry , Heterocyclic Compounds/chemistry , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/pharmacokinetics , Lymphocytes/drug effects , Receptors, Lysosphingolipid/agonists , Animals , Cells, Cultured , Immunosuppressive Agents/chemical synthesis , Lymphocytes/cytology , Male , Models, Molecular , Molecular Structure , Rats, Inbred Lew , Structure-Activity RelationshipABSTRACT
Optimization of the novel alpha-2-delta-1 ligand 4 provided compounds 37 and 38 which have improved DMPK profiles, good in vivo analgesic activity and in vitro selectivity over alpha-2-delta-2. An in-house P-gp prediction programme and the MetaSite software package were used to help solve the specific problems of high P-gp efflux and high in vivo clearance.
Subject(s)
Analgesics/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels/chemistry , Neuralgia/drug therapy , Pyrazoles/chemistry , Pyridazines/chemistry , Pyridines/chemistry , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analgesics/chemical synthesis , Analgesics/therapeutic use , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/therapeutic use , Calcium Channels/metabolism , Calcium Channels, L-Type , Ligands , Pyrazoles/chemical synthesis , Pyridazines/chemical synthesis , Pyridazines/therapeutic use , Pyridines/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
N-(3-fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.
Subject(s)
Drug Discovery , Gastrointestinal Agents/pharmacology , Piperazines/pharmacology , Piperidines/pharmacology , Pyloric Antrum/drug effects , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Dogs , Gastrointestinal Motility/drug effects , Humans , Muscle Contraction/drug effects , Piperazines/chemistry , Piperidines/chemistry , Pyloric Antrum/physiology , Rabbits , RatsABSTRACT
Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.
Subject(s)
Carbon/chemistry , Pyridines/chemistry , Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Animals , Chemistry, Pharmaceutical/methods , Drug Design , Gastrins/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Pyridines/chemical synthesis , Pyridines/pharmacology , Rabbits , Rats , Receptors, Gastrointestinal Hormone/chemistry , Receptors, Neuropeptide/chemistryABSTRACT
The key step in an attempted biomimetic synthesis of the indole-diterpene mycotoxin emindole SB delivers the pentacyclic compound resulting from 6-endo cyclisation instead of the product arising by the 5-exo reaction required in the putative biosynthetic pathway.