Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series

G Protein-Coupled Receptor 119 (GPR119) Agonists for the Treatment of Diabetes: Recent Progress and Prevailing Challenges

“…Because of its favorable rat PK (low clearance and volume of distribution, high oral bioavailability, and good terminal half-life) 56 was investigated in different acute and chronic rodent models. 68 For example, in a four-week study in ZDF rats (oral dose of 1, 3, or 10 mg/kg qd), 56 showed significant fed glucose lowering after two weeks of treatment and improved HbA 1c levels at day 28 in a dosedependent manner (1.63%, 1.85% and 2.58%, respectively, relative to vehicle) without any signs of tachyphylaxis in that period.…”

“…Arena identified a cyclohexyl ring as a replacement for the central pyrimidine ring in 4. 68 The 1,4-trans-cyclohexyl diether motif, as exemplified in the pyrazine derivative 55, was preferred over other geometries (cis-1,4-or cis/trans-1,3disubstitution) and may be considered as another way of rigidization in the spacer region. Compound 55 showed full agonism at human and rat GPR119 (hEC 50 = 5.9 nM, 110% IA; rEC 50 = 64.0 nM, 110% IA) and exhibited the lowest plasma protein binding among compounds with different (het)aryl head groups as indicated by the smallest potency shift in the presence of bovine serum albumin in the in vitro assay.…”

“…Arena identified a cyclohexyl ring as a replacement for the central pyrimidine ring in 4 . The 1,4- trans -cyclohexyl diether motif, as exemplified in the pyrazine derivative 55 , was preferred over other geometries ( cis -1,4- or cis / trans -1,3-disubstitution) and may be considered as another way of rigidization in the spacer region.…”

“…Exploration of the SAR of the piperidine tail groups led to the chiral carbamate 56 , a potent GPR119 agonist (hEC 50 = 3.0 nM, 106% IA, active across species) with good metabolic stability in human liver microsomes and human hepatocytes and a clean profile regarding hERG channel and CYP enzyme inhibition. Because of its favorable rat PK (low clearance and volume of distribution, high oral bioavailability, and good terminal half-life) 56 was investigated in different acute and chronic rodent models . For example, in a four-week study in ZDF rats (oral dose of 1, 3, or 10 mg/kg qd), 56 showed significant fed glucose lowering after two weeks of treatment and improved HbA 1c levels at day 28 in a dose-dependent manner (1.63%, 1.85% and 2.58%, respectively, relative to vehicle) without any signs of tachyphylaxis in that period.…”

Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

“…As a result, GPR119 agonists are used for discovery of anti-T2DM agents by lowering the blood glucose level and improving b-cells function. Indeed, numerous synthetic, small molecule GPR119 agonists were revealed by academia and industry to date, and some of which have advanced into clinical trials such as MBX-2982, BMS-903452, LEZ763, ZYG-19 [18][19][20][21][22][23][24][25][26][27][28][29][30] . Despite tremendous endeavours, none of GPR119 agonists were approved to market by FDA up to now.…”