Reproducibility and Validity of a Questionnaire Measuring Treatment Burden on Patients with Type 2 Diabetes: Diabetic Treatment Burden Questionnaire (DTBQ)

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Discovery of DS-1558: A Potent and Orally Bioavailable GPR40 Agonist

GPR40 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR40 agonists stimulate insulin secretion in the presence of high glucose concentration. On the basis of this mechanism, GPR40 agonists are possible novel insulin secretagogues with reduced or no risk of hypoglycemia. The improvement of <i>in vitro</i> activity and metabolic stability of compound <b>1</b> led to the discovery of <b>13</b>, (3<i>S</i>)-3-ethoxy-3-(4-{[(1<i>R</i>)-4-(trifluoromethyl)-2,3-dihydro-1<i>H</i>-inden-1-yl]­oxy}­phenyl)­propanoic acid, as a potent and orally available GPR40 agonist. Compound <b>13</b> (DS-1558) was found to have potent glucose lowering effects during an oral glucose tolerance test in ZDF rats

Aminopyrazole–Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies

Herein, we report the lead optimization of amrinone–phenylalanine based GPR142 agonists. Structure–activity relationship studies led to the discovery of aminopyrazole–phenylalanine carboxylic acid <b>22</b>, which exhibited good agonistic activity, high target selectivity, desirable pharmacokinetic properties, and no cytochrome P450 or hERG liability. Compound <b>22</b>, together with its orally bioavailable ethyl ester prodrug <b>23</b>, were found to be suitable for in vivo proof-of-concept studies. Compound <b>23</b> displayed good efficacy in a mouse oral glucose tolerance test (OGTT). Compound <b>22</b> showed GPR142 dependent stimulation of insulin secretion in isolated mouse islets and demonstrated a statistically significant glucose lowering effect in a mouse model bearing transplanted human islets

Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes

GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic β-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound <b>1</b> toward a proof of concept compound <b>33</b>, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys