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    • Finally we investigated increasing basicity as a way to

    2022-05-31

    Finally, we investigated increasing basicity as a way to improve solubility. We expected that conversion of the ether linkage of to an -methyl group could improve solubility. More than expected, 1080 6 demonstrated significant improvement of values of solubility for the two media, especially for acidic medium (JP1). The agonistic activity of was only about three times less than . Optimization of led to compounds and which exhibited good solubility and acceptable agonistic activity. Metabolic stability of was moderate (percentage remaining at 1 h = 77% in human liver microsomes, 44% in rat liver microsomes), whereas exhibited high metabolic stability as shown in . Further optimization of was carried out with the aim of enhancing agonistic activity, while maintaining good solubility and metabolic stability (). Cyclized products and with favorable profiles in solubility and metabolic stability, especially the indoline derivative , showed about three times improvement in agonistic activity compared with . This result suggested that steric repulsion between the substituent at the 5-position of the pyrimidine and the -methyl group attenuated the agonistic activity of and , when compared with the ether forms and , respectively. Therefore, compound without the methyl group at the 5-position of pyrimidine in was synthesized and evaluated. As a result, improvement of agonistic activity (EC = 19 nM) was observed while maintaining good solubility and metabolic stability. The lipophilicity of (Clog P = 3.6) was considerably lower than that of (Clog P = 5.1), resulting in a better LLE value (4.0). We finally succeeded in identifying a novel GPR119 agonist which exhibited reduced lipophilicity compared with and additionally demonstrated good solubility and metabolic stability. The pharmacokinetic profiles of compound were evaluated in Sprague-Dawley rats (). Compound exhibited long-lasting and good oral availability. In addition, showed no inhibitory activity (IC > 50 μM) against all six CYP isoforms (CYP 3A4, 2D6, 1A2, 2C9, 2C8, 2C19). The effect of compound on plasma glucose levels in the intraperitoneal glucose tolerance test (ipGTT) in Sprague-Dawley rats was evaluated. Glucose solution was intraperitoneally administered at 16 h after oral administration of (10 mg/kg) or vehicle. The plasma glucose levels were measured at 0, 30 and 60 min after glucose loading. Plasma glucose levels just before glucose loading were slightly different between the vehicle and groups. The plasma glucose levels at 30 and 60 min after glucose loading in group were 14% and 11% lower than that in the vehicle group, respectively. Compound suppressed the increase in peak plasma glucose levels after glucose loading. In summary, lead generation studies guided by LLE led to the identification of compound having a spirocyclic cyclohexane structure, which was a versatile right side moiety in GPR119 agonists. Further efforts to improve solubility succeeded in discovery of a novel GPR119 agonist . Compound exhibited orally active, long-lasting pharmacokinetic profiles and showed a hypoglycemic effect after 16 h of administration in rats. Further identification of novel GPR119 agonists with a spirocyclic cyclohexane structure will be reported in due course. Acknowledgments
    Regulation of glucose homeostasis is crucial to mammalian life. Insulin secretion from pancreatic β-cells regulates increases in glucose levels and glucose uptake in peripheral tissues. Insulin resistance, which refers to the inability of body tissues to respond properly to endogenous insulin, develops because of several factors, including genetics, obesity, increasing age, and the presence of high blood sugar over a long period of time. These factors finally cause one of the most serious chronic diseases, type 2 diabetes mellitus (T2DM; non-insulin dependent diabetes), which eventually induces various complications such as renal failure, blindness, neuropathy, and cardiovascular disorders. More than 90% of patients with diabetes are classified as having T2DM and the number of people with T2DM is expected to increase to 330 million by 2030. Currently, various types of hypoglycemic agents, including sulfonylureas, thiazolidinediones, glucagon-like peptide-1 (GLP-1) analogs, dipeptidyl peptidase-4 (DPP4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, are used for the treatment of T2DM. However, some patients still fail to achieve desired blood glucose levels despite the use of these agents. Most of these drugs cause side effects, including hypoglycemia, weight gain, and loss of therapy responsiveness. Therefore, there is a clear need for a drug with a new mechanism of action that demonstrates improved efficacy and safety over currently available drugs.