Nonpeptide alphavbeta3 antagonists. Part 11: discovery and preclinical evaluation of potent alphavbeta3 antagonists for the prevention and treatment of osteoporosis.
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Coleman
Paul J
PJ
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
Brashear
Karen M
KM
Askew
Ben C
BC
Hutchinson
John H
JH
McVean
Carol A
CA
Duong
Le T
LT
Feuston
Bradley P
BP
Fernandez-Metzler
Carmen
C
Gentile
Michael A
MA
Hartman
George D
GD
Kimmel
Donald B
DB
Leu
Chih-Tai
CT
Lipfert
Lorraine
L
Merkle
Kara
K
Pennypacker
Brenda
B
Prueksaritanont
Thomayant
T
Rodan
Gideon A
GA
Wesolowski
Gregg A
GA
Rodan
Sevgi B
SB
Duggan
Mark E
ME
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008253:Macaca mulatta; D008958:Models, Molecular; D009287:Naphthyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010024:Osteoporosis / Q000188:drug therapy* / Q000517:prevention & control; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C492677:3-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-(1,8)naphthyridin-2-yl)nonanoic acid; C492676:3-pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-(1,8)naphthyridin-2-yl)nonanoic acid; D016023:Integrins; D009287:Naphthyridines; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5