3-Nitro-4-amino benzoic acids and 6-amino nicotinic acids are highly selective agonists of GPR109b Philip J. Skinner, a, * Martin C. Cherrier, a Peter J. Webb, a Carleton R. Sage, a Huong T. Dang, b Cameron C. Pride, b Ruoping Chen, b Susan Y. Tamura, a Jeremy G. Richman, b Daniel T. Connolly b and Graeme Semple a a Medicinal Chemistry, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA b Discovery Biology, Arena Pharmaceuticals, 6166 Nancy Ridge Drive, San Diego, CA 92121, USA Received 3 August 2007; revised 14 September 2007; accepted 14 September 2007 Available online 19 September 2007 Abstract—A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective ago- nists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and sev- eral analogues showed comparable activity to the nitroaryl series. Ó 2007 Elsevier Ltd. All rights reserved. The discovery that the human G-protein coupled recep- tors GPR109a (HM74A) and GPR109b (HM74) are high and low affinity receptors, respectively, for niacin (1)(Fig. 1) has garnered significant recent attention. 1,2 Niacin has been used for many years for the treatment of lipid disorders including dyslipidemia, for the preven- tion of atherosclerosis, and is of particular interest be- cause of its ability to raise levels of high density lipoproteins (HDL). 3 Evidence suggests that the anti- lipolytic activity of niacin (1) is mediated by GPR109a and not via GPR109b, 4 indeed, the function of GPR109b currently remains unknown. However, given the identical receptor coupling, the high homology and the significant overlap in the expression profile between GPR109a and GPR109b, it is likely that activation of GPR109b could also inhibit lipolysis. A challenge in the development of GPR109b as a molec- ular target remains the lack of a rodent ortholog. Given the high (95% identity) homology between the two receptors, GPR109b appears to have arisen from a very late gene duplication of GPR109a. GPR109a has a rodent ortholog, PUMA-G, 5 whereas GPR109b does not, and a search of publicly available genomes only identified the presence of a GPR109b ortholog in chim- panzee. Lower species, including even Rhesus monkey, showed no evidence of the receptor. However, the identification of ligands selective for GPR109b could provide useful tools for further exploring the pharma- cology of this receptor. A selective activator of GPR109b may display an anti-lipolytic response, and hence provide an alternative strategy for the therapeutic control of lipid levels. Furthermore, it is possible that selective GPR109b activators may avoid the char- acteristic and uncomfortable cutaneous flushing re- sponse elicited by niacin in humans. 6 Niacin induced flushing has been shown to be mediated by PUMA- G, 7 and via receptor expressed in epidermal Langerhans cells. 8 Thus minor expressional changes between GPR109a and GPR109b may eliminate the flushing re- sponse and avoid this unpleasant side effect of GPR109a activation. 0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2007.09.058 Keywords: Niacin; GPR109a; GPR109b; HM74; HM74A; PUMA-G; HDL; Lipolysis. * Corresponding author. Tel.: +1 858 4537200x1680; fax: +1 858 4537210; e-mail: pskinner@arenapharm.com Figure 1. Ligands for GPR109a and GPR109b. Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 17 (2007) 6619–6622