Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis.
3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
Hutchinson
John H
JH
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. john_hutchinson@merck.com
Halczenko
Wasyl
W
Brashear
Karen M
KM
Breslin
Michael J
MJ
Coleman
Paul J
PJ
Duong
Le T
LT
Fernandez-Metzler
Carmen
C
Gentile
Michael A
MA
Fisher
John E
JE
Hartman
George D
GD
Huff
Joel R
JR
Kimmel
Donald B
DB
Leu
Chih-Tai
CT
Meissner
Robert S
RS
Merkle
Kara
K
Nagy
Rose
R
Pennypacker
Brenda
B
Perkins
James J
JJ
Prueksaritanont
Thomayant
T
Rodan
Gideon A
GA
Varga
Sandor L
SL
Wesolowski
Greg A
GA
Zartman
Amy E
AE
Rodan
Sevgi B
SB
Duggan
Mark E
ME
D000818:Animals; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D004285:Dogs; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D008297:Male; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010024:Osteoporosis / Q000188:drug therapy / Q000517:prevention & control; D010052:Ovariectomy; D010084:Oxidation-Reduction; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C478626:3-(6-methoxypyridin-3-yl)-3-(2-oxo-3-(3-(5,6,7,8-tetrahydro(1,8)naphthyridin-2-yl)propyl)imidazolidin-1-yl)propionic acid; D039302:Integrin alphaVbeta3; D009287:Naphthyridines; D011422:Propionates