Discovery of a Potent Thiadiazole Class of Histamine H₃ Receptor Antagonist for the Treatment of Diabetes

A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H₃ receptor antagonists. The 4-(5-([1,4′-bipiperidin]-1′-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)­morpholine (<b>5u</b>) displayed excellent potency and ex vivo receptor occupancy. Compound <b>5u</b> was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, <b>5u</b> dose dependently blocked the increase of HbA_1c after 12 days of treatment

Discovery of SCH 900188: A Potent Hepatitis C Virus NS5B Polymerase Inhibitor Prodrug As a Development Candidate

Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound <b>1</b>, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound <b>11</b> demonstrated excellent potency. Its C2 <i>N</i>,<i>N</i>-dimethylaminoethyl ester prodrug <b>12</b> (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate