ABSTRACT
Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.
Subject(s)
Receptors, Gastrointestinal Hormone/agonists , Receptors, Neuropeptide/agonists , Sulfonamides/pharmacology , Sulfones/pharmacology , Animals , Binding Sites , CHO Cells , Chemistry, Pharmaceutical , Cricetinae , Cricetulus , Drug Design , Drug Discovery , Models, Chemical , Molecular Structure , 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.
