title: A novel series of indazole-/indole-based glucagon receptor antagonists.
abstract: A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: songnian.lin@merck.com.
authors: Songnian
authors: S
authors: Lin
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Fengqi
authors: F
authors: Zhang
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Guoqiang
authors: G
authors: Jiang
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Sajjad A
authors: SA
authors: Qureshi
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Xiaodong
authors: X
authors: Yang
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Gary G
authors: GG
authors: Chicchi
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Laurie
authors: L
authors: Tota
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Alka
authors: A
authors: Bansal
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Edward
authors: E
authors: Brady
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Maria
authors: M
authors: Trujillo
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Gino
authors: G
authors: Salituro
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Corey
authors: C
authors: Miller
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: James R
authors: JR
authors: Tata
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Bei B
authors: BB
authors: Zhang
authors: Early Development and Discovery Science, and Preclinical Development, Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States.
authors: Emma R
authors: ER
authors: Parmee
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000737:chemistry* / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D015394:Molecular Structure; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D007191:Indazoles; D007211:Indoles; D018027:Receptors, Glucagon
keywords: Diabetes; Glucagon receptor antagonist; Glucose lowering; Indazole; Indole