RESUMEN
A series of γ-lactam prostaglandin E(1) analogs bearing a 16-phenyl moiety in the ω-chain and aryl moiety in the α-chain were synthesized and biologically evaluated. Among the tested compounds, γ-lactam PGE analog 3 designed as a structural hybrid of 1 and 2 was discovered as the most optimized EP2/EP4 dual agonist with excellent subtype-selectivity (K(i) values: mEP2=9.3 nM, mEP4=0.41 nM). A structure-activity relationship study is presented.
Asunto(s)
Alprostadil/análogos & derivados , Lactamas/química , Subtipo EP2 de Receptores de Prostaglandina E/química , Subtipo EP4 de Receptores de Prostaglandina E/química , Animales , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Cinética , Modelos Químicos , Conformación Molecular , RatasRESUMEN
A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes.