Small molecule antagonists of the CCR2b receptor. Part 2: Discovery process and initial structure–activity relationships of diamine derivatives Wilna J. Moree, a, * Ken-ichiro Kataoka, b Michele M. Ramirez-Weinhouse, a,  Tatsuki Shiota, b Minoru Imai, b Masaki Sudo, b,à Takaharu Tsutsumi, b Noriaki Endo, b Yumiko Muroga, b Takahiko Hada, b,§ Hiroko Tanaka, b Takuya Morita, b Jonathan Greene, a Doug Barnum, a John Saunders, a,– Yoshinori Kato, b Peter L. Myers a,k and Christine M. Tarby a, ** a Deltagen Research Laboratories,    4570 Executive Drive, Suite 400, San Diego, CA 92121, USA b Teijin Institute for Bio-medical Research, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan Received 6 October 2003; accepted 5 August 2004 Available online 16 September 2004 Abstract—Structure–activity relationships (SAR) of a weakly active class of CCR2b inhibitors were utilized to initiate a lead evo- lution program employing the Drug Discovery Engine TM . Several alternative structural series have been discovered that display nanomolar activity in the CCR2b binding and CCR2b-mediated chemotaxis assays. Ó 2004 Elsevier Ltd. All rights reserved. Chemokines (chemotactic cytokines) are a family of small molecular weight proteins involved in a variety of inflammatory responses via the chemoattraction and activation of leukocytes. 1 Monocyte chemoattractant protein-1 (MCP-1) is a 8–10 kDa protein belonging to the b- or CC chemokine subfamily and is postulated to be primarily responsible for the selective recruitment of leukocytes from the circulation to the site of inflam- mation 2 by binding to its 7-transmembrane G protein- coupled receptor (CCR2b) on the surface of monocytes and macrophages. Both CCR2b 3 and MCP-1 4 knockout mice as well as animal model studies with anti-MCP-1 have indicated that therapeutic intervention at the CCR2b receptor may have beneficial effects in a variety of inflammatory diseases including rheumatoid arthri- tis, 5 atherosclerosis, 6 glomerulonephritis, 7 and multiple sclerosis. 8 For this reason, we and others 9 have initiated programs to develop small molecule CCR2b antago- nists. Screening of the Teijin sample collection, followed by hit to lead efforts, led to the identification of lead ser- ies 1 and 2 (Fig. 1). 10 Despite optimization efforts, using both traditional medicinal chemistry and library-based approaches to identify potent CCR2b inhibitors in this series, binding 0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2004.08.009 * Corresponding author at present address: Neurocrine Biosciences, Inc., 12790 El Camino Real, San Diego, CA 92130, USA. Tel.: +1 858 617 7506; fax: +1 858 617 7998; e-mail: wmoree@neurocrine. com   Present address: Pfizer Global Research and Development, La Jolla Laboratories, 3550 General Atomics Court, San Diego, CA 92121, USA. à Present address: Pfizer Global Research and Development, Nagoya Laboratories, 5-2 Taketoyo, Aichi 470-2393, Japan. § Present address: Bizen Chemical Co., Ltd, Research and Develop- ment Department, 363-Tokutomi, Kumayama-Cho, Akaiwa-Gun, Okayama 709-0716, Japan. – Present address: see *. k Present e-mail address: myerspl@mindspring.com ** Present address: Bristol-Myers Squibb Company, PO Box 4000, Princeton, NJ 08543, USA.    Formerly CombiChem, Inc. N N R R 2 N R 2 R 1 N N R 1 R 1 2 R 1 N R Figure 1. Homopiperazine lead series and alternative structural series. Bioorganic & Medicinal Chemistry Letters 14 (2004) 5413–5416