Discovery of 3-Piperidinyl-1-cyclopentanecarboxamide as a Novel Scaffold for Highly Potent CC Chemokine Receptor 2 Antagonists

Abstract

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).

Chemokine receptor antagonists: Part 1

“…A number of companies have disclosed CCR2 antagonists, including Merck which has been very active in the field reporting CCR2 antagonists in both the peer reviewed [83][84][85][86][87][88][89][90] and the patent literature [91][92][93][94][95][96][97][98] . An extensive Structure Activity Relationship (SAR) approach around a screening hit from the Merck sample collection yielded compound 55, a benzyl piperidine derivative, ( Figure 2 , compound 1) which displays a good binding affinity (IC 50 = 39 nM) in cells expressing recombinant human CCR2 and inhibited CCL2-induced chemotaxis (IC 50 = 9.6 nM) [86] .…”

Chemical Biology of Cell Motility Inhibitors

“…Other reports of antagonist discovery are summarized as follows: NSC651016 (4) and AMD3100 (5) antagonize CXCR4, an antagonistic compound against CCR2B with MCP-1 (CCL2), 3-peperidinyl-1-cyclopentane carboxamide as a specific, potent antagonist against CCR2, and so on [16][17][18]. Given those reports, it appears a quite remarkable strategy to set a molecular target in searching for anti-inflammatory agents, a reverse chemical genetic approach; however, there is also a forward chemical genetic approach.…”

Synthesis of spiroheterocycles derived from benzo[f]chromanone

“…Proliferation of research in spiro chemistry has now attained considerable height, right from the unprecedented synthesis of spiro hydrocarbon by Bayer [1]. Spiro heterocycles in particular fused at a central carbon atom display diverse biological and pharmaceutical [2–7] activities due to their interesting conformational features and structural implications. The presence of the sterically constrained spiro structure in various natural products also generates interest in the investigation on spiro compound [8, 9].…”