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.

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.

MeSH terms

  • Animals
  • Bone Density / drug effects
  • Bone Resorption / drug therapy
  • Bone Resorption / etiology
  • Bone Resorption / metabolism
  • Dogs
  • Female
  • Humans
  • Integrin alphaVbeta3 / antagonists & inhibitors*
  • Macaca mulatta
  • Male
  • Naphthyridines / chemical synthesis*
  • Naphthyridines / chemistry
  • Naphthyridines / pharmacology
  • Osteoporosis* / drug therapy
  • Osteoporosis* / prevention & control
  • Ovariectomy
  • Oxidation-Reduction
  • Propionates / chemical synthesis*
  • Propionates / chemistry
  • Propionates / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 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
  • Integrin alphaVbeta3
  • Naphthyridines
  • Propionates