In summary through medicinal chemistry design and computer a

In summary, through medicinal chemistry design and computer-assisted conformational modeling, the initial lead was evolved into a series of dihydrobenzofuran derivatives, , as potent GPR119 agonists. Optimization of general structure at various regions of the molecule, including the substituent on dihydrobenzofuran, the R attachment on the right-hand piperidine nitrogen, and the left-hand piperidine/piperazine and its attachment R led to the identification of compounds and as potent human GPR119 modulators with favorable metabolic stability, ion channel activity, and PXR profiles and as potential candidates for further in vivo evaluation.
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease characterized by hyperglycemia due to impaired insulin secretion and insulin resistance. The number of people with T2DM worldwide is more than 300 million, and the prevalence is rapidly increasing., Long-term complications such as heart disease, organ failure, and lower limb amputations are the major risk factor for T2DM patients. Although a variety of treatments are available for T2DM, many patients are unable to achieve their target glycemic control. Therefore, new drugs with novel mode of action that exhibit improved efficacy and safety relative to current available medications are clearly needed. G Protein coupled receptor 119 (GPR119) is a class A type receptor, which is expressed primarily in pancreatic β-cells and the K and L aphidicolin synthesis of the gastrointestinal tract., Some endogenous natural agonists of GPR119, such as oleoylethanolamide (OEA) and -oleoyldopamine (OLDA), have been identified and investigated for their biological effects., However, because of their instability and weak activity, it’s not practical to develop it directly as a clinical drug. GPR119 agonists could stimulate secretion of the incretins, glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic peptide (GIP) from L-cells , and increase the release of insulin from pancreatic β-cells., , , , These results significantly indicate GPR119 agonists have a dual mechanism for lowing plasma glucose and potential diabetes control. Arena researchers disclosed the first potent and oral small molecule agonist of GPR119, in the form of AR231453 (). Compound AR231453 displayed the strong agonistic activity (EC=0.68 nM) and improved oral glucose tolerance in wild-type mice but not in GPR119 deficient mice. Following with this enthusiasm, many pharmaceutical companies and institutes were pursuing GPR119 agonists for the treatment of type 2 diabetes., , , , , , To date, some GPR119 agonists have been progressed to the clinical phases (APD668, APD597, PSN821, GSK1292263, MBX-2982, DS-8500a, BMS-903452, LEZ763, ZYG-19) as shown in ., , , , , , In our efforts to discover small molecule full agonist of GPR119, pyrimidine compound AR231453 was selected as lead structure. As disclosed in our previously papers, derivatives and bearing -nortropanol/amine exhibited strong and full GPR119 agonistic activities (EC in the nanomolar range, )., Based on the exciting results, optimization of lead compound was conducted via retaining 5-nitropyrimidine and replacing piperidine with conformation restricted diverse azabicyclic ethers or amines. We estimated that introduction of rigid fragments like / azabicyclic rings to the ligands that reduced the conformational flexibility to make an ideal conformation and best recognition by the receptor. Herein, we report synthesis of a series of 5-nitropyrimidine derivatives with / azabicyclic fragments as potential GPR119 agonists for the treatment of type 2 diabetes. The azabicyclic intermediates – were synthesized following the procedures and conditions as shown in . The Diels-Alder reaction of cyclopentadiene, ammonium chloride and formaldehyde in water gave alkene compound, which was then protected by a Boc group. Transformation of alkene into a mixture of alcohol and was achieved using a hydroboration-oxidation reaction. Amines – were prepared from alcohols and via a 3 steps sequence of PCC oxidation followed by reductive amination and debenzylation., The azabicyclic rings – were generated from ketone via similar methods with intermediates –. The ketone was obtained by the aza Diels-Alder reaction, which was converted to compound via replacement of -methoxyphenyl group (PMP) with Boc group. Reduction of with NaBH gave a mixture alcohol and with a ratio of 1.2/1. The synthetic pathway of amines – was same with – by reductive amination and debenzylation. The stereochemistry of all intermediates – was determined based on H NMR data and published procedures., , , , The methyne contiguous with nitrogen or oxygen in bicyclic configuration isomers showed different splitting signal in H NMR spectra.