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    • br Experimental br Acknowledgments This research

    2021-09-17


    Experimental
    Acknowledgments This research was supported by the Korea Research Foundation (2013R1A1A2007509). The authors thank to Dr. Moon Ho Son (Dong-A Pharm. Co. Ltd) for hGPR119 agonist activity assay. We also thank to Pharmacal Research Institute and Central Laboratory of Kangwon National University for the use of analytical instruments and bioassay facilities.
    Type 2 PF-CBP1 hydrochloride (T2DM) caused by insulin resistance and loss of β-cell function is a serious metabolic disorder that has reached pandemic proportions worldwide. Due to a lack of effective and safe long-term treatments for this chronic disease, there is a strong demand for novel therapeutic approaches. GPR119, a class A GPCR, is highly expressed in insulin producing pancreatic β-cells and incretin releasing intestinal endocrine cells. Activation of GPR119 elevates intracellular cAMP levels, triggering glucose-dependent insulin secretion from β-cells and incretin (e.g., GLP-1 and GIP) release from intestinal cells., GLP-1 and GIP promote β-cell viability and also stimulate insulin secretory activity by interacting with their receptors expressed on β-cells., Hence, orally acting GPR119 agonists may constitute a new therapy for improvement of glucose tolerance in patients with T2DM. Importantly, GPR119 mediated glucose control is expected to be associated with a low risk of hypoglycemia due to its glucose-dependent mechanism of action. We previously disclosed the discovery of APD597 () and its favorable preclinical and clinical profile., Following this, we recently reported a 5-fluoro-4,6-dialkoxypyrimidine series (e.g., ) that exhibited improved in vitro agonist efficacy and possessed reduced CYP2C9 inhibitory potential. Thus far, our prototypical GPR119 agonists have had a central pyrimidine pharmacophore as a preferred structural feature. With the goal of identifying alternatives to this preferred motif, we replaced the pyrimidine with a cyclohexane ring (e.g., , , ). The 1,3-diether derivative () was devoid of activity at the human GPR119 receptor (EC >100μM), however, the 1,4-diether analogue (, a mixture /) possessed modest agonist activity in a (EC >200nM). Encouraged by this result, we separated the two geometric isomers (- and -) to determine if the orientation of the functional groups was important for receptor activity. The superior potency of the - isomer verified the importance of this geometric configuration (), and led us to the discovery of a novel 1,4-dioxycyclohexane GPR119 agonist series. SAR studies began with an investigation of the aryloxy group in an attempt to identify a motif with the best balance of potency, efficacy, and physicochemical properties (). The isomers depicted in were prepared in a similar manner as described in . Alternatively, a Mitsunobu reaction employing -4-((1-methylpiperidin-4-yl)oxy)cyclohexanol (-) and a corresponding aromatic alcohol was also effective. Several aromatic rings such as phenyl (, , and ), picoline (), and pyrazine (, ) were well tolerated in conjunction with a methyl sulfone or nitrile. Presumably, these substituents provide a favorable hydrogen bonding acceptor interaction with GPR119 and contribute to the potency observed. Of the more potent compounds prepared, exhibited the smallest potency shift in the presence of serum, correlating well with the order of log (<<<). Notably, this new series was associated with a very high intrinsic activity ( >100) at both human and rat GPR119 receptors. Ultimately, the 5-(methylsulfonyl)pyrazine () was selected as the preferred aryloxy group for further SAR investigation. We next turned our SAR effort toward exploration of the piperidine substitution (). Piperidine motifs incorporating carbamates (, –), amides (–), fluorinated alkyl groups (–), and heteroaromatic rings (–) were prepared. These were introduced in the final steps of the synthesis as illustrated in . Trifluoromethyl analogues (–), in particular, displayed significantly improved potency relative to our clinical compound () and were stable in human, rat, and mouse liver microsomes. Amide attained good potency and had a low shift in the serum shift assay, but suffered from significantly reduced microsomal stability in mouse. Tertiary amines (–) comprised of fluorinated alkyls led to a reduction in GPR119 activity and reduced microsomal stability (e.g., ). Based on the combination of in vitro potency and microsomal stability, a handful of compounds were selected for further consideration. Compound possessed a similar potency and PK profile relative to , however this enantiomer was less effective in increasing glucose excursion in an oGTT experiment performed in 129SVE mice. The exceedingly potent hexafluoro analogue () was removed from further consideration as it impaired physical mobility of rodents in a dose dependent manner. Additionally, we were concerned that the activated -hexafluoroisopropyl (HFIP) carbamate may form a covalent bond with serine hydrolases. Oxadiazole analogues – showed reduced GIP release in normoglycemic 129SVE mice relative to , despite their overall good potency, stability, and pharmacokinetic properties. For the reasons described above, selected for further analysis.