| 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 theαvβ3 receptor. This compound has an excellent in vitro profile (IC50 = 0.08 nM), a significantunbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesusmonkey. On the basis of the efficacy shown in three in vivo models of bone turnover, thecompound was selected for clinical development. To support the ongoing metabolism and safetystudies, a novel strategy was employed in which a series of oxidized derivatives of 6 wereprepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These productsproved useful in the identification of active metabolites generated by either in vitro or in vivometabolism.
|
