g-Lactams as glycinamide replacements in cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 8; pp. 2425 - 2430
• Main Authors: Cherney, Robert J, Mo, Ruowei, Meyer, Dayton T, Voss, Matthew E, Yang, Michael G, Santella, Joseph B, Duncia, John V, Lo, Yvonne C, Yang, Gengjie, Miller, Persymphonie B, Scherle, Peggy A, Zhao, Qihong, Mandlekar, Sandhya, Cvijic, Mary Ellen, Barrish, Joel C, Decicco, Carl P, Carter, Percy H
• Format: Journal Article
• Language: English
• Published: 15-04-2010
• ISSN: 0960-894X
• DOI: 10.1016/j.bmcl.2010.03.035

We describe the design, synthesis, and evaluation, of g-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC sub(50) = 1.0 nM and chemotaxis IC sub(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.