Synthesis and SAR of heterocyclic carboxylic acid isosteres based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity Mark Hadden a, * , Allan Goodman a , Cheng Guo a , Peter R. Guzzo a , Alan J. Henderson a , Kevin Pattamana a , Megan Ruenz a , Bruce J. Sargent a , Brian Swenson a , Larry Yet a , Jian Liu b , Shuwen He b , Iyassu K. Sebhat b , Linus S. Lin b , Constantin Tamvakopoulos e , Qianping Peng e , Yanqing Kan c , Oksana Palyha c , Theresa M. Kelly c , Xiao-Ming Guan c , Joseph M. Metzger d , Marc L. Reitman c , Ravi P. Nargund b a AMRI, 26 Corporate Circle, Albany, NY 12212, USA b Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA c Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA d Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA e Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA article info Article history: Received 7 January 2010 Revised 3 March 2010 Accepted 5 March 2010 Available online 12 March 2010 Keywords: BRS-3 Obesity Acid isosteres abstract SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described. Ó 2010 Elsevier Ltd. All rights reserved. According to the CDC’s Behavioral Risk Factor Surveillance Sys- tem, over the past 20 years there has been a dramatic increase in obesity in young adults in the United States, with only one state having an obesity prevalence of less than 20%. 1,2 This high rate of occurrence combined with obesity being a risk factor in a wide range of diseases 3 such as type 2 diabetes, cardiovascular diseases and cancer make it an important indication for pharmaceutical intervention. Moreover, currently marketed drugs such as sibutr- amine 4 and orilstat 5 have unsatisfactory efficacy and undesirable side effects that limit their prescription amongst the general population. Bombesin receptor subtype-3 (BRS-3 or BB3), is an orphan G- protein coupled receptor (GPCR) with high sequence identity to BB1 and BB2 (50%) and is located primarily in the hypothalamus and testes. 6 Preclinical validation of BRS-3’s role in energy homeo- stasis has been demonstrated with genetically altered mice lacking the BRS-3 receptor, causing induction of obesity, hypertension and diabetes. 7 Through a combination of high-throughput screening and SAR development, a potent small molecule BRS-3 agonist 1 8 was dis- covered (Fig. 1). The carboxylic acid was mapped around the biphenyl ring (structures not shown); however, all of these compounds lost po- tency compared to 1. Interestingly, extending the acid moiety away from the ring maintained good potency in compound 2 (Table 1). Further SAR studies were pursued to improve oral bioavailabil- ity and brain penetration whilst retaining binding and functional agonism at the human BRS-3 receptor. Replacement of the carbox- ylic acid group in compound 1 with traditional acid isosteres such as tetrazole 1a and phenol 1b provided good binding and func- 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.03.028 * Corresponding author. Tel.: +1 518 512 2835; fax: +1 518 512 2079. E-mail address: mark.hadden@amriglobal.com (M. Hadden). N HN COOH 1 N HN 2 O CO 2 H Figure 1. Bioorganic & Medicinal Chemistry Letters 20 (2010) 2912–2915 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl