br Materials and methods br Results br Discussion br

Materials and methods
Results
Discussion
Disclosures
Author contributions
Acknowledgements
Introduction Diabetes mellitus is one of the fastest growing chronic diseases worldwide, with an estimated prevalence of 382 million patients, of which about 90% have type 2 diabetes mellitus (T2DM) [1]. A ten-year shorter life expectancy is associated in patients diagnosed with T2DM. This is partly due to a number of complications with which it is associated, including cardiovascular disease, ischemic heart disease, stroke and lower limb amputations [2], [3]. In clinical therapy for T2DM, hypoglycemic agents such as insulin, metformin, thiazolidinediones (TZDs), sulfonylurea derivatives (SUs), glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase 4 (DPP4) inhibitors are used [4]. All current diabetes drugs have known adverse effects. For example, insulin and its analogs have adverse effects such as potentially fatal hypoglycemic events and weight gain, accompanied by the difficulty in administration through injection. There is a strong need for novel oral antidiabetic drugs with a minimum adverse effects profile [5]. GPR119 is a G-protein coupled receptor predominantly expressed on certain enteroendocrine ion channel (L and K cells) in the small intestine and β-cells within the islets of Langerhans of the pancreas [6]. Several endogenous lipid metabolites were shown to be GPR119 agonists, such as oleoylethanolamide (OEA), N-oleoyl-dopamine (OLDA), 1-oleoyl-lysophosphatidylcholine and 2-oleoylglycerol [7]. The activation of GPR119 increases intracellular cAMP levels, leading to enhanced glucose-dependent insulin secretion, release of incretin and improved glucose homeostasis [8]. GPR119 agonists have been shown to improve glucose tolerance and preserve beta cell function in both rodents and humans [9], [10], [11], [12], [13]. Compound AR231453, the first potent and orally efficacious GPR119 agonist, was discovered by Semple’s group [9]. Following this discovery, several pharmaceutical companies and academic institutes pursued GPR119 agonists as potential drug candidates for the treatment of T2DM [14], [15], [16], [17], [18], [19]. As a result several GPR119 agonists have been developed as clinical treatments for T2DM, as shown in Fig. 1[20]. As disclosed in our precedent paper [21], hit compounds 1 and 2 (Fig. 2) bearing endo-azabicyclic amine and alcohol exhibited potent (EC50 in the nanomolar range) and full GPR119 agonistic activities. In order to improve agonistic efficacy, we optimized hit compounds 1 and 2 with retaining 5-nitropyrimidine with an endo-azabicyclic alcohol or amine fragment. N-Boc was replaced with isosteric alkyl carbamates and its surrogates. Also, several aromatic amines or alcohols were introduced as congeners of the 2-fluoro-4-methylsulfonylphenylamino group. Based on the available structure–activity relationship (SAR) data, most GPR119 agonists contain two important pharmacophores: an aryl or heteroaryl moiety substituted with a hydrogen-bond accepting group, and a piperidine moiety N-capped with a carbamate or an isosteric heterocycle [22]. Therefore, it is surmised that the novel series of agonists could cause significant pharmacological changes. This is a report of the synthesis and biological evaluation of 5-nitropyrimidine with endo-azabicyclic amine/alcohol derivatives as potential GPR119 agonists.
Results and discussion
Conclusion In conclusion, we synthesized and evaluated a new series of 5-nitropyrimidine derivatives bearing endo-azabicyclic alcohols/amines as GPR119 agonists. Most compounds exhibited stronger EC50 values than that of OEA. Among them, analogs bearing endo-azabicyclic alcohols displayed more potent GPR119 activation activities than compounds with endo-azabicyclic amine. Analogs containing fluoro substituted aromatic ring was favorable for agonistic activity. Compounds (6, 7, 8, 12, 17) exhibited potent biological activities (nano mole grade EC50 values) and were proved as full agonists. Especially, analog 8 with isopropyl carbamate substituted endo-azabicyclic alcohol posessed the best EC50 value (0.6nM) with good agonistic activity (103% max). Compound 12 containing cyclopropylsulfonyl substituted endo-azabicyclic alcohol showed quite good agonistic activity (116.7% max) with strong EC50 value (1.6nM). Generally 2-fluoro substitution of the aryl group at the C4 position of 5-nitropyrimidine scaffold resulted in the increase of biological activity as shown in Table 2. These valuable results encourage us to conduct further research in vitro and in vivo that will be reported in due course.