title: Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.
abstract: Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.
authors.affiliation: Research and Development, Bristol-Myers Squibb, Co. , P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ellsworth
authors.forename: Philip M
authors.initials: PM
authors.lastname: Sher
authors.forename: Ximao
authors.initials: X
authors.lastname: Wu
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Richard B
authors.initials: RB
authors.lastname: Sulsky
authors.forename: Zhengxiang
authors.initials: Z
authors.lastname: Gu
authors.forename: Natesan
authors.initials: N
authors.lastname: Murugesan
authors.forename: Yeheng
authors.initials: Y
authors.lastname: Zhu
authors.forename: Guixue
authors.initials: G
authors.lastname: Yu
authors.forename: Doree F
authors.initials: DF
authors.lastname: Sitkoff
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Carlson
authors.forename: Liya
authors.initials: L
authors.lastname: Kang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Yang
authors.forename: Ning
authors.initials: N
authors.lastname: Lee
authors.forename: Rose A
authors.initials: RA
authors.lastname: Baska
authors.forename: William J
authors.initials: WJ
authors.lastname: Keim
authors.forename: Mary Jane
authors.initials: MJ
authors.lastname: Cullen
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Azzara
authors.forename: Eva
authors.initials: E
authors.lastname: Zuvich
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thomas
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Rohrbach
authors.forename: James J
authors.initials: JJ
authors.lastname: Devenny
authors.forename: Helen E
authors.initials: HE
authors.lastname: Godonis
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Harvey
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Murphy
authors.forename: Gerry G
authors.initials: GG
authors.lastname: Everlof
authors.forename: Paul I
authors.initials: PI
authors.lastname: Stetsko
authors.forename: Olafur
authors.initials: O
authors.lastname: Gudmundsson
authors.forename: Susan
authors.initials: S
authors.lastname: Johnghar
authors.forename: Asoka
authors.initials: A
authors.lastname: Ranasinghe
authors.forename: Kamelia
authors.initials: K
authors.lastname: Behnia
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Pelleymounter
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D055808:Drug Discovery; D006207:Half-Life; D011485:Protein Binding; D011724:Pyridazines / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000493:pharmacokinetics*
chemical_list: D011724:Pyridazines; D043884:Receptor, Cannabinoid, CB1; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System