title: 1-Sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists for the treatment of obesity.
abstract: A novel series of 1-sulfonyl-4-acylpiperazines as selective cannabinoid-1 receptor (CB1R) inverse agonists was discovered through high throughput screening (HTS) and medicinal chemistry lead optimization. Potency and in vivo properties were systematically optimized to afford orally bioavailable, highly efficacious, and selective CB1R inverse agonists that caused food intake suppression and body weight reduction in diet-induced obese rats and dogs. It was found that the receptor binding assay predicted in vivo efficacy better than functional antagonist/inverse agonist activities. This observation expedited the structure-activity relationship (SAR) analysis and may have implications beyond the series of compounds presented herein.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. petr_vachal@merck.com
authors.forename: Petr
authors.initials: P
authors.lastname: Vachal
authors.forename: Joan M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Cathy C R-R
authors.initials: CC
authors.lastname: Huang
authors.forename: Julie
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authors.lastname: Lao
authors.forename: Jing C
authors.initials: JC
authors.lastname: Xiao
authors.forename: Chun-Pyn
authors.initials: CP
authors.lastname: Shen
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
authors.forename: Lauren
authors.initials: L
authors.lastname: Shearman
authors.forename: Sloan
authors.initials: S
authors.lastname: Stribling
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Chen
authors.forename: Andrea
authors.initials: A
authors.lastname: Frassetto
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Richard G
authors.initials: RG
authors.lastname: Ball
authors.forename: Nancy N
authors.initials: NN
authors.lastname: Tsou
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Hickey
authors.forename: Donald F
authors.initials: DF
authors.lastname: Thompson
authors.forename: Terry D
authors.initials: TD
authors.lastname: Faidley
authors.forename: Susan
authors.initials: S
authors.lastname: Nicolich
authors.forename: Joana
authors.initials: J
authors.lastname: Achanfuo-Yeboah
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hora
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann