2. Academic Validation
  3. Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis

Nonpeptide alphavbeta3 antagonists. 8. In vitro and in vivo evaluation of a potent alphavbeta3 antagonist for the prevention and treatment of osteoporosis

  • J Med Chem. 2003 Oct 23;46(22):4790-8. doi: 10.1021/jm030306r.
John H Hutchinson 1,  Wasyl Halczenko,  Karen M Brashear,  Michael J Breslin,  Paul J Coleman,  Le T Duong,  Carmen Fernandez-Metzler,  Michael A Gentile,  John E Fisher,  George D Hartman,  Joel R Huff,  Donald B Kimmel,  Chih-Tai Leu,  Robert S Meissner,  Kara Merkle,  Rose Nagy,  Brenda Pennypacker,  James J Perkins,  Thomayant Prueksaritanont,  Gideon A Rodan,  Sandor L Varga,  Greg A Wesolowski,  Amy E Zartman,  Sevgi B Rodan,  Mark E Duggan
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. [email protected]
PMID: 14561098 DOI: 10.1021/jm030306r
Abstract

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.

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