title: Discovery of novel, potent, and orally active spiro-urea human glucagon receptor antagonists.
abstract: A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, PO Box 2000, RY50G-146, Rahway, NJ 07065, USA. dongming_shen@merck.com
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Shen
authors.forename: Fengqi
authors.initials: F
authors.lastname: Zhang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Brady
authors.forename: Mari Rios
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: Jasminka
authors.initials: J
authors.lastname: Dragovic
authors.forename: William P
authors.initials: WP
authors.lastname: Feeney
authors.forename: Guoquiang
authors.initials: G
authors.lastname: Jiang
authors.forename: Peggy E
authors.initials: PE
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: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
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; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D018027:Receptors, Glucagon; D013141:Spiro Compounds; D014508:Urea