RESUMEN
A series of 6-(4-amino-1-piperidinyl)carbonyl-2(1H)-quinolinones, and their open form derivatives, were synthesized and evaluated for their ability to stimulate femoral artery blood flow (FBF) in the canine hindlimb. All members of this series stimulated FBF, and subsequent experiments revealed that selected members of this series produced minimal changes in coronary blood flow or systemic blood pressure. Compound 25 was the most promising agent in this respect, and clinical trials are now ongoing to evaluate the effectiveness of this drug as a novel treatment for intermittent claudication and Raynaud's phenomenon.
Asunto(s)
Miembro Posterior/irrigación sanguínea , Piperidinas/síntesis química , Vasodilatadores/síntesis química , Animales , Arterias , Presión Sanguínea/efectos de los fármacos , Circulación Coronaria/efectos de los fármacos , Perros , Fémur/irrigación sanguínea , Técnicas In Vitro , Piperidinas/química , Piperidinas/farmacología , Quinolonas/síntesis química , Quinolonas/química , Quinolonas/farmacología , Flujo Sanguíneo Regional/efectos de los fármacos , Relación Estructura-Actividad , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
The synthesis and evaluation of both the (R)- and (S)-enantioisomers about the 5-position on a tetrahydro-1H-1-benzazepine derivative were described. The absolute configuration of the (R,R)-isomer (10) was determined by X-ray crystallographic analysis. After evaluation of both enantiomers (compounds R-2, S-2) for binding affinity, cAMP accumulation, and an in vivo study using Brattleboro rats, R-2 showed more potent activity as a V(2) receptor agonist than S-2.