RESUMO
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.
Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Administração Oral , Animais , Quimiotaxia , Cães , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Macaca mulatta , Modelos Químicos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Amidas/síntese química , Carbono/química , Química Farmacêutica/métodos , Ciclopentanos/química , Ciclopentanos/síntese química , Receptores de Quimiocinas/antagonistas & inibidores , Receptores de Quimiocinas/metabolismo , Animais , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Leucócitos/metabolismo , Masculino , Camundongos , Peso Molecular , Ratos , Ratos Sprague-Dawley , Receptores CCR2 , Relação Estrutura-AtividadeRESUMO
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).
