RESUMEN
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.
Asunto(s)
Analgésicos/química , Bloqueadores de los Canales de Calcio/química , Canales de Calcio/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Piridazinas/química , Piridinas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Analgésicos/síntesis química , Analgésicos/uso terapéutico , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio/metabolismo , Canales de Calcio Tipo L , Ligandos , Pirazoles/síntesis química , Piridazinas/síntesis química , Piridazinas/uso terapéutico , Piridinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Fármacos Gastrointestinales/farmacología , Piperazinas/farmacología , Piperidinas/farmacología , Antro Pilórico/efectos de los fármacos , Receptores de la Hormona Gastrointestinal/agonistas , Receptores de Neuropéptido/agonistas , Animales , Perros , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Contracción Muscular/efectos de los fármacos , Piperazinas/química , Piperidinas/química , Antro Pilórico/fisiología , Conejos , RatasRESUMEN
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.