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Discovery of a potent thiadiazole class of histamine h3 receptor antagonist for the treatment of diabetes.

ABSTRACT: 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 (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u 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, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.

SUBMITTER: Rao AU

PROVIDER: S-EPMC4025655 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Discovery of a potent thiadiazole class of histamine h3 receptor antagonist for the treatment of diabetes.

Rao Ashwin U AU Shao Ning N Aslanian Robert G RG Chan Tin-Yau TY Degrado Sylvia J SJ Wang Li L McKittrick Brian B Senior Mary M West Robert E RE Williams Shirley M SM Wu Ren-Long RL Hwa Joyce J Patel Bhuneshwari B Zheng Shuqin S Sondey Christopher C Palani Anandan A

ACS medicinal chemistry letters 20111121 3

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 (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u 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-tr ...[more]

PMID: 24900450

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