Synthesis and SAR of 1,2,3,4-tetrahydroisoquinolin-1-ones as novel G-protein-coupled receptor 40 (GPR40) antagonists Paul S. Humphries * , John W. Benbow, Paul D. Bonin, David Boyer, Shawn D. Doran, Richard K. Frisbie, David W. Piotrowski, Gayatri Balan, Bruce M. Bechle, Edward L. Conn, Kenneth J. Dirico, Robert M. Oliver, Walter C. Soeller, James A. Southers, Xiaojing Yang Pfizer Global R&D, Eastern Point Road, Groton, CT 06340, USA article info Article history: Received 4 February 2009 Revised 16 March 2009 Accepted 20 March 2009 Available online 25 March 2009 Keywords: Diabetes GPR40 Tetrahydroisoquinolinones Ligand efficiency abstract The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein- coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported. Ó 2009 Elsevier Ltd. All rights reserved. Type 2 diabetes (T2D), the most commonly occurring form of diabetes, is a condition in which the body resists the insulin that is produced by the pancreas and may fail to make enough insulin to maintain normal glucose levels. 1 The incidence of T2D has in- creased worldwide in recent years, largely because of growing rates of obesity, and is likely to grow to greater than 366 million by the year 2030. 2 One of the recently characterized G-protein-coupled receptor (GPCR) families is the GPR40–43 family, 3 comprising GPR40, 41 and 43. 4 These three family members share  30–40% sequence identity. Three independent groups have identified GPR40 as a receptor for medium- (C6–C12) and long-chain (C14–C24) fatty acids (FAs). 5 GPR40 is preferentially expressed in the pancreas with elevated levels reported in the islets and also in the pancreatic b-cell lines. 6 GPR40-deficient b-cells secrete less insulin in response to FAs, and loss of GPR40 protects mice from obesity-in- duced hyperinsulinemia, increased hepatic glucose output, yperglycemia and glucose intolerance. 7 Conversely, overexpression of GPR40 in b-cells of mice leads to impaired cell function, hypoin- sulinemia and diabetes. These results suggest that GPR40 plays a critical role in linking obesity and T2D. Efforts toward the identification of 1,2,3,4-tetrahydroisoquino- lin-1-ones as novel GPR40 antagonists are reported here. A high- throughput screen (HTS) of the Pfizer compound collection identi- fied compounds 1 and 2 (Fig. 1) as antagonists of GPR40. These hits were extremely attractive based on their high ligand efficiency, 8 low human liver microsomal (HLM) clearance and promising selec- tivity in an initial selectivity panel. The above properties motivated an initiation of hit-to-lead chemistry to explore the activity of this class of compounds as GPR40 antagonists. Initial efforts involved exploration of the SAR of the terminal cyclohexyl and phenyl moieties of 1 and 2. In order to do this in an efficient manner, a concise synthesis of phenol intermediate 7 was required. Intermediate 7 could then be utilized for late stage diversification and efficient SAR exploration of this region of the molecule. Phenol 7 was accessed in a straightforward fashion following the five step protocol below (Scheme 1). 4-Benzyloxybenzaldehyde 3 was condensed with propylamine to afford imine 4 in excellent yield. Treatment of imine 4 with homophthalic anhydride resulted in the formation of cis-lactam 5 in moderate yield along with minor 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.03.082 * Corresponding author. Tel.: +1 860 705 0559. E-mail address: phumphri@gmail.com (P.S. Humphries). Figure 1. Initial hits from high-throughput screening. Bioorganic & Medicinal Chemistry Letters 19 (2009) 2400–2403 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl