Literature DB >> 24900450

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

Ashwin U Rao1, Ning Shao1, Robert G Aslanian1, Tin-Yau Chan1, Sylvia J Degrado1, Li Wang1, Brian McKittrick1, Mary Senior1, Robert E West1, Shirley M Williams1, Ren-Long Wu1, Joyce Hwa1, Bhuneshwari Patel1, Shuqin Zheng1, Christopher Sondey1, Anandan Palani1.   

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.

Entities:  

Keywords:  H3; HbA1c; Histamine; antagonist; non-fasting glucose; thiadiazole; type 2 diabetes

Year:  2011        PMID： 24900450      PMCID： PMC4025655          DOI： 10.1021/ml200250t

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


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