Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity Roger A. Smith, a, * Zahra Fathi, b Furahi Achebe, a Christiana Akuche, a Su-Ellen Brown, b Soongyu Choi, a Jianmei Fan, a Susan Jenkins, c Harold C. E. Kluender, a Anish Konkar, b Rico Lavoie, a Ronald Mays, c Jennifer Natoli, b Stephen J. O’Connor, a Astrid A. Ortiz, b Ning Su, a Christy Taing, b Susan Tomlinson, a Theresa Tritto, b Gan Wang, a Stephan-Nicholas Wirtz, d Wai Wong, a Xiao-Fan Yang, a Shihong Ying a and Zhonghua Zhang a a Department of Chemistry Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA b Department of Metabolic Disorders Research, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA c Department of Research Technologies, Bayer HealthCare, Pharmaceuticals Division, West Haven, CT 06516, USA d Bayer HealthCare AG, Pharma Research, D-42096 Wuppertal, Germany Received 12 January 2007; revised 1 March 2007; accepted 1 March 2007 Available online 12 March 2007 Abstract—Several imidazole-based cyclohexyl amides were identified as potent CB-1 antagonists, but they exhibited poor oral expo- sure in rodents. Incorporation of a hydroxyl moiety on the cyclohexyl ring provided a dramatic improvement in oral exposure, together with a ca. 10-fold decrease in potency. Further optimization provided the imidazole 2-hydroxy-cyclohexyl amide 45, which exhibited hCB-1 K i = 3.7 nM, and caused significant appetite suppression and robust, dose-dependent reduction of body weight gain in industry-standard rat models. Ó 2007 Elsevier Ltd. All rights reserved. Obesity and excessive body weight are now recognized as serious health concerns, as these conditions are associated with decreased life span and several medical complications such as diabetes, hyperlipidemia, coro- nary artery disease, osteoarthritis, and some cancers. 1 Furthermore, with the prevalence of obesity increasing rapidly and current therapies being considered largely inadequate, 2 obesity has been declared one of the most significant health problems faced by mankind. 3 During the last decade, antagonism of the cannabi- noid type 1 receptor (CB-1) has been pursued as a highly promising strategy for the treatment of obesity. 4 To date, one CB-1 antagonist, the 1,5-diaryl- pyrazole hydrazide rimonabant (1, SR-141716, Sanofi- Aventis), has been approved in the European Union for the treatment of obese or overweight patients with associated risk factors, such as type 2 diabetes or dyslipidemia. 5 Of the various structure classes reported as CB-1 antago- nists, the majority incorporate a central core fragment substituted by two aromatic rings and a hydrogen bond donor/acceptor functionality such as a carboxamide group. 4 Indeed, the pyrazole core exemplified in 1 has been effectively replaced with other 5-membered hetero- cycles such as dihydropyrazole, 6 triazole, 7–9 thiazole, 8,10 pyrrole, 11,12 and imidazole. 7,8,13–15 For example, the 1,2- diaryl-imidazole hydrazide 2 was reported by researchers at Neurocrine Biosciences 7 and Solvay 8 to exhibit human CB-1 K i values of 85 and 23 nM, respectively. In our assay, hCB-1 K i = 7.8 nM was determined for 2. 14 The related cyclohexyl amide 3 was investigated as an isosteric analog by Neurocrine Biosciences and was found to have somewhat superior potency 7 (hCB-1 K i = 3.9 nM was obtained for 3 in our assay). In this report, we describe our investigation and optimization of 1,2-diaryl-imida- zole amides related to 3 as effective CB-1 antagonists. 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.03.011 Keywords: Cannabinoid; Antagonist; Obesity; Appetite suppressant. * Corresponding author at present address: Angiotech Pharmaceuti- cals, Inc., 1618 Station Street, Vancouver, BC, Canada V6A-1B6. Tel.: +1 604 221 6927; e-mail: rosmith@angio.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 2706–2711