Nonpeptide αvβ3 Antagonists. Part 11: Discovery and Preclinical Evaluation of Potent αvβ3 Antagonists for the Prevention and Treatment of Osteoporosis
| Autor: | Lorraine Lipfert, Gideon A. Rodan, John H. Hutchinson, Bradley P. Feuston, Kara Merkle, Donald B. Kimmel, Thomayant Prueksaritanont, Mark E. Duggan, Carol A. Mcvean, Chih-Tai Leu, Gregg Wesolowski, Brenda L Pennypacker, Michael A. Gentile, Ben C. Askew, Sevgi B. Rodan, Le T. Duong, Karen M. Brashear, Carmen Fernandez-Metzler, Paul J. Coleman, George D. Hartman |
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| Rok vydání: | 2004 |
| Předmět: |
Models
Molecular Integrins Ovariectomy Drug Evaluation Preclinical Nonanoic acid Administration Oral Biological Availability Pharmacology Rats Sprague-Dawley Inhibitory Concentration 50 Structure-Activity Relationship chemistry.chemical_compound Dogs Pharmacokinetics Bone Density Oral administration In vivo Drug Discovery Animals Humans Receptors Vitronectin Bone Resorption Naphthyridines Receptor IC50 Dose-Response Relationship Drug Chemistry Biological activity Macaca mulatta In vitro Rats Biochemistry Osteoporosis Molecular Medicine Female |
| Zdroj: | Journal of Medicinal Chemistry. 47:4829-4837 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049874c |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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