Nonpeptide αvβ3 Antagonists. Part 11:  Discovery and Preclinical Evaluation of Potent αvβ3 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 αvβ3 receptor. These compounds have excellent in vitro pr...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2004-09, Vol.47 (20), p.4829-4837
Main Authors: Coleman, Paul J, Brashear, Karen M, Askew, Ben C, Hutchinson, John H, McVean, Carol A, Duong, Le T, Feuston, Bradley P, Fernandez-Metzler, Carmen, Gentile, Michael A, Hartman, George D, Kimmel, Donald B, Leu, Chih-Tai, Lipfert, Lorraine, Merkle, Kara, Pennypacker, Brenda, Prueksaritanont, Thomayant, Rodan, Gideon A, Wesolowski, Gregg A, Rodan, Sevgi B, Duggan, Mark E
Format: Article
Language:English
Subjects:
Biological and medical sciences
Bones, joints and connective tissue. Antiinflammatory agents
Medical sciences
Pharmacology. Drug treatments
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 αvβ3 receptor. These compounds have excellent in vitro profiles (IC50 = 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049874c