Nonpeptide alpha V beta 3 antagonists. Part 10: In vitro and in vivo evaluation of a potent 7-methyl substituted tetrahydro-[1,8]naphthyridine derivative.
Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.
Breslin
Michael J
MJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. michael_breslin@merck.com
Duggan
Mark E
ME
Halczenko
Wasyl
W
Hartman
George D
GD
Duong
Le T
LT
Fernandez-Metzler
Carmen
C
Gentile
Michael A
MA
Kimmel
Donald B
DB
Leu
Chih-Tai
CT
Merkle
Kara
K
Prueksaritanont
Thomayant
T
Rodan
Gideon A
GA
Rodan
Sevgi B
SB
Hutchinson
John H
JH
D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009287:Naphthyridines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats
D039302:Integrin alphaVbeta3; D009287:Naphthyridines