title: Discovery of cyclic guanidines as potent, orally active, human glucagon receptor antagonists.
abstract: In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model.
authors: Discovery and Preclinical Sciences, Merck Research Laboratories, Rahway, NJ 07065, USA. christopher_sinz@merck.com
authors: Christopher
authors: C
authors: Sinz
authors: Jiang
authors: J
authors: Chang
authors: Ashley Rouse
authors: AR
authors: Lins
authors: Ed
authors: E
authors: Brady
authors: Mari
authors: M
authors: Candelore
authors: Qing
authors: Q
authors: Dallas-Yang
authors: Victor
authors: V
authors: Ding
authors: Guoqiang
authors: G
authors: Jiang
authors: Zhen
authors: Z
authors: Lin
authors: Steven
authors: S
authors: Mock
authors: Sajjad
authors: S
authors: Qureshi
authors: Gino
authors: G
authors: Salituro
authors: Richard
authors: R
authors: Saperstein
authors: Jackie
authors: J
authors: Shang
authors: Deborah
authors: D
authors: Szalkowski
authors: Laurie
authors: L
authors: Tota
authors: Stella
authors: S
authors: Vincent
authors: Michael
authors: M
authors: Wright
authors: Shiyao
authors: S
authors: Xu
authors: Xiaodong
authors: X
authors: Yang
authors: Bei
authors: B
authors: Zhang
authors: James
authors: J
authors: Tata
authors: Ronald
authors: R
authors: Kim
authors: Emma
authors: E
authors: Parmee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003500:Cyclization; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D004195:Disease Models, Animal; D004285:Dogs; D055808:Drug Discovery; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D006146:Guanidines; D007004:Hypoglycemic Agents; D018027:Receptors, Glucagon