文摘
Introduction of ring restrictions to a linear aminobutyramideCC chemokine receptor 2 (CCR2) antagonist lead (2) led to thediscovery of a 1,3-disubstituted cyclopentane scaffold with enhancedhCCR2 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 alsoshowed activity against the mouse CCR2 receptor with an IC50 of 130nM. Compound 16 is selective against other chemokine receptors,including CCR5 (~500-fold).