title: 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.
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ashwin U
authors.initials: AU
authors.lastname: Rao
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ning
authors.initials: N
authors.lastname: Shao
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Aslanian
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Tin-Yau
authors.initials: TY
authors.lastname: Chan
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Degrado
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: McKittrick
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Mary
authors.initials: M
authors.lastname: Senior
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: West
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Williams
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Ren-Long
authors.initials: RL
authors.lastname: Wu
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Joyce
authors.initials: J
authors.lastname: Hwa
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Bhuneshwari
authors.initials: B
authors.lastname: Patel
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Shuqin
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sondey
authors.affiliation: Department of Medicinal Chemistry and Cardiovascular/Metabolic Disease, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
authors.forename: Anandan
authors.initials: A
authors.lastname: Palani
keywords: H3; HbA1c; Histamine; antagonist; non-fasting glucose; thiadiazole; type 2 diabetes