Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control Graeme Semple a,⇑ , Albert Ren a , Beatriz Fioravanti a , Guillherme Pereira a , Imelda Calderon a , Karoline Choi a , Yifeng Xiong a , Young-Jun Shin a , Tawfik Gharbaoui a , Carleton R. Sage a , Michael Morgan b , Charles Xing c , Zhi-Liang Chu c , James N. Leonard c , Andrew J. Grottick c , Hussein Al-Shamma c , Yin Liang d , Keith T. Demarest d , Robert M. Jones a a Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA b DMPK, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA c Discovery Biology, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA d Johnson & Johnson Pharmaceutical Research & Development, LLC. Spring House, PA 19477, USA article info Article history: Received 17 January 2011 Revised 28 February 2011 Accepted 2 March 2011 Available online 13 March 2011 Keywords: GPR119 agonists GPCR Diabetes GDIS abstract We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-pro- tein coupled receptor GPR119, a target that has been of significant recent interest in the field of metab- olism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the intro- duction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes. Ó 2011 Elsevier Ltd. All rights reserved. We have recently described the identification of GPR119 (also termed glucose-dependent insulinotropic receptor, or GDIR) as a constitutively active, pancreatic b-cell-expressed G-protein cou- pled receptor (GPCR) whose activation can elevate intracellular cAMP levels in both transfected CHO cells and pancreatic b-cell lines. 1 Such activity would be expected to stimulate glucose- dependent insulin release from b-cells. In addition, we showed that GPR119 could stimulate incretin hormone release from cells local- ized in the GI tract and thus the receptor might be capable of reg- ulating glucose homeostasis by multiple mechanisms. 2 These early target validation studies suggested that GPR119 may be an inter- esting target for the treatment of type 2 diabetes that may be ame- nable to the discovery of orally acting agents. GPR119 can be activated by phospholipids and lipid amides in vitro, 3,4 but it remains unclear as to whether these are physiologi- cally important ligands. A role for lipid amides in the activation of GPR119 could be implied by its phylogenetic proximity to cannab- inoid receptors. 5 However, the potency and efficacy of these puta- tive ligands at the GPR119 receptor is modest and some examples are also known to modulate other biological targets, including PPARa nuclear receptors and TRPV1 channels. 6 Lipid amides might also be expected to possess poor stability in vivo. Hence, the dis- covery of AR231453 (1a, Fig. 1) was essential for initial investiga- tions into the role of this target in plasma glucose control. 7 However, whereas 1a was an excellent tool for acute studies in mouse, it had a number of drawbacks. The relatively poor exposure in rat and the toxicity observed after multiple doses of 1a in mouse (which may in part have been a consequence of the vehicle mix- tures it was necessary to use as a result of poor solubility) meant that it was not suitable for examining the effect of GPR119 modu- lation in any of the known and well characterized chronic models of diabetes in rodents. Hence we undertook to look for alternative structures to demonstrate activity in proof of concept experiments of a chronic or sub-chronic nature, with the long term goal of iden- tifying a compound suitable for clinical testing. Starting from our prototypical GPR119 agonist 1a, we were keen to investigate the effect of removing both the undesirable ani- line and nitro portions of the molecule simultaneously by intro- ducing a simple 6,5-fused ring system. We envisioned that such a modification would maintain several of the hydrogen bond acceptor interactions that we believed may be important for activ- ity, such as the two nitrogens in the pyrimidine ring and the sul- fone portion, and these would be held in a similar position to those in 1a by introduction of this constraint to a key dihedral an- gle. 8 The resulting compound (2), which could be prepared in four 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.03.007 ⇑ Corresponding author. Tel.: +1 858 453 7200; fax: +1 858 453 7210. E-mail address: gsemple@arenapharm.com (G. Semple). Bioorganic & Medicinal Chemistry Letters 21 (2011) 3134–3141 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl