RESUMO
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.
Assuntos
Descoberta de Drogas , Fármacos Gastrointestinais/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Antro Pilórico/efeitos dos fármacos , Receptores dos Hormônios Gastrointestinais/agonistas , Receptores de Neuropeptídeos/agonistas , Animais , Cães , Motilidade Gastrointestinal/efeitos dos fármacos , Humanos , Contração Muscular/efeitos dos fármacos , Piperazinas/química , Piperidinas/química , Antro Pilórico/fisiologia , Coelhos , RatosRESUMO
A series of 1-(biphenylmethylamidoalkyl)-pyrimidones has been designed as nanomolar inhibitors of recombinant lipoprotein-associated phospholipase A(2) with high potency in whole human plasma. 5-(Pyrazolylmethyl) derivative 16 and 5-(methoxypyrimidinylmethyl) derivative 27 demonstrated excellent pharmacodynamic profiles which correlated well with their pharmacokinetic effects.