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.
