title: Discovery of novel, potent, selective, and orally active human glucagon receptor antagonists containing a pyrazole core.
abstract: A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, RY50G-346, Rahway, NJ 07065, USA. dongming.shen@merck.com
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brady
authors.forename: Mari R
authors.initials: MR
authors.lastname: Candelore
authors.forename: Qing
authors.initials: Q
authors.lastname: Dallas-Yang
authors.forename: Victor D-H
authors.initials: VD
authors.lastname: Ding
authors.forename: William P
authors.initials: WP
authors.lastname: Feeney
authors.forename: Guoquiang
authors.initials: G
authors.lastname: Jiang
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
authors.forename: Steve
authors.initials: S
authors.lastname: Mock
authors.forename: Sajjad A
authors.initials: SA
authors.lastname: Qureshi
authors.forename: Richard
authors.initials: R
authors.lastname: Saperstein
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Shen
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Laurie M
authors.initials: LM
authors.lastname: Tota
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wright
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Zheng
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Emma R
authors.initials: ER
authors.lastname: Parmee
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D011720:Pyrazoles; D018027:Receptors, Glucagon