Nonpeptide alpha V beta 3 antagonists. Part 9: Improved pharmacokinetic profile through the use of an aliphatic, des-amide backbone.
A series of alphaVbeta3 receptor antagonists lacking the amide bond of previously-reported 'chain-shortened' compounds is described. Replacement of the lone amide bond with two methylene groups in this series yields more lipophilic compounds that have longer half-lives, lower clearance, and greater oral bioavailability when administered to dogs.
Whitman
David B
DB
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. david_whitman@merck.com
Askew
Ben C
BC
Duong
Le T
LT
Fernandez-Metzler
Carmen
C
Halczenko
Wasyl
W
Hartman
George D
GD
Hutchinson
John H
JH
Leu
Chih-Tai
CT
Prueksaritanont
Thomayant
T
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Duggan
Mark E
ME
D000818:Animals; D001557:Benzenesulfonates / Q000737:chemistry* / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007462:Iodobenzenes / Q000737:chemistry* / Q000493:pharmacokinetics*
D001557:Benzenesulfonates; D039302:Integrin alphaVbeta3; D007462:Iodobenzenes; C032365:benzenesulfonic acid