Acknowledgments This research was supported

Acknowledgments This research was supported by the Korea Research Institute of Chemical Technology (KRICT) funded by the Ministry of Science, ICT & Future Planning (KK1703-G00, KK1707-C05, SI1707-02, KK-1607-C09, and SKO1707C05) and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare (BB-1403).
GPR119 is a G protein-coupled receptor (GPCR) expressed predominantly in pancreatic beta AP20187 and the gastrointestinal tract. Activation of GPR119 promotes secretion of incretins such as glucagon-like peptide-1 (GLP-1) in the intestinal tract and glucose-dependent release of insulin in pancreatic beta cells. Therefore, it is expected that GPR119 agonists have the potential to be useful for the treatment of type 2 diabetes with low-risk of hypoglycemia. Numerous synthetic GPR119 agonists have been reported so far, some of which have advanced into clinical trials (). Most of the reported GPR119 agonists are composed of three parts as depicted in : a piperidine or a piperazine ring -substituted with a carbamate or a heteroaryl group at the right side, a phenyl group substituted with a methylsulfonyl or a heteroaryl group (X) at the left side, and a linker part connecting the two parts (). In particular, the -substituted piperidine or piperazine ring at the right side is a characteristic structure in many GPR119 agonists. Here we report potent GPR119 agonists with novel spirocyclic cyclohexane structures which differ from the substituted piperidine or piperazine ring at the right side. In starting our research, we were interested in PSN119-1M among the reported agonists since it had a flexible ether linker, the length of which could be adjusted in one carbon units. In addition to that, we expected the flexible linker allowed the molecule to take various relative conformations between the right and left side part, increasing the possibility that the molecule would bind to the GPR119 receptor appropriately. Therefore, we chose PSN119-1M as a starting point. GPR119 activity was evaluated for the human GPR119 receptor in a cell-based cAMP assay. The results expressed the potency as EC values and the inherent activities (IA) as percentages which were compared to the test compound with oleoylethanolamide (OEA), an endogenous ligand of GPR119 (defined as 100% activation). In order to simplify the synthesis, a 4-methylsulfonylphenyl group was chosen as the left side functionality. We explored lengths of the linker and the left side substituent (X) (). Compound , having the same length of an ether linker (three carbons) as PSN119-1M, showed agonistic activity with an EC value of 353 nM. Compound , having an ether linker one carbon unit longer than , provided less than 2-fold improvement in agonistic activity. Further extension of the length of an ether linker to five carbons (compound : EC = 14 nM) enhanced agonistic activity more than 25-fold compared with . On the other hand, compound with a six carbon ether linker was less active than and appeared to be a partial agonist (EC = 78 nM, IA = 72%). As a result, showed the highest agonistic activity among –, indicating that a five carbon long ether linker is optimum. However, solubility of (15.9 μM in Fed State Simulated Intestinal Fluid (FeSSIF)) was poor. With the aim of increasing solubility, we next explored a substituent on the benzene ring at the left side. We found that dimethylcarbamoyl derivative showed not only improved FeSSIF solubility (74.2 μM), but also higher GPR119 activity (EC = 5 nM), indicating that the dimethylcarbamoyl group was favorable as a substituent for the left side part. To further improve solubility by lowering lipophilicity and to secure stability against acid, we replaced the -butoxy carbonyl (Boc) group of with an isopropoxy carbonyl group. Compared with , the isopropyl carbamate had even better solubility (221.8 μM in FeSSIF) and comparable agonistic activity (EC = 10 nM). We therefore selected the ether group with a methylene chain consisting of five carbons as a linker and the benzene ring having a dimethylcarbamoyl group at the 4-position as left side moiety in order to explore the right side moiety.