RESUMEN
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Asunto(s)
Química Farmacéutica/métodos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/química , Administración Oral , Animales , Quimiotaxis , Perros , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Modelos Químicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Introduction of ring restrictions to a linear aminobutyramide CC chemokine receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3'R)-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine receptors, including CCR5 ( approximately 500-fold).
Asunto(s)
Amidas/síntesis química , Ciclopentanos/síntesis química , Piperidinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Amidas/química , Amidas/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Ciclopentanos/química , Ciclopentanos/farmacología , Humanos , Técnicas In Vitro , Ratones , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Piperidinas/química , Piperidinas/farmacología , Receptores CCR2 , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of low molecular weight antagonists of both the human and murine CC chemokine receptor 2, containing a 1-alkyl-3-(3-methyl-4-spiroindenylpiperidine)-substituted cyclopentanecarboxamide, is described. A SAR study of the C(1) substituent revealed that short, branched alkyl groups such as isopropyl, isobutyl, or cyclopropyl are optimal for both human and murine CCR2 binding activity.