227752-09-2Relevant articles and documents
Non-peptide αvβ3 antagonists. Part 7: 3-Substituted tetrahydro-[1,8]naphthyridine derivatives
Wang, Jiabing,Breslin, Michael J.,Coleman, Paul J.,Duggan, Mark E.,Hunt, Cecilia A.,Hutchinson, John H.,Leu, Chih-Tai,Rodan, Sevgi B.,Rodan, Gideon A.,Duong, Le T.,Hartman, George D.
, p. 1049 - 1052 (2004)
A series of 3-substituted tetrahydro-[1,8]naphthyridine containing αvβ3 antagonists was prepared. A comparison of their in vitro IC50 values to the electron properties of the 3-substituents revealed a good linear Hammett c
Nonpeptide αvβ3 Antagonists. 8. In Vitro and in Vivo Evaluation of a Potent αvβ3 Antagonist for the Prevention and Treatment of Osteoporosis
Hutchinson, John H.,Halczenko, Wasyl,Brashear, Karen M.,Breslin, Michael J.,Coleman, Paul J.,Duong, Le T.,Fernandez-Metzler, Carmen,Gentile, Michael A.,Fisher, John E.,Hartman, George D.,Huff, Joel R.,Kimmel, Donald B.,Leu, Chih-Tai,Meissner, Robert S.,Merkle, Kara,Nagy, Rose,Pennypacker, Brenda,Perkins, James J.,Prueksaritanont, Thomayant,Rodan, Gideon A.,Varga, Sandor L.,Wesolowski, Greg A.,Zartman, Amy E.,Rodan, Sevgi B.,Duggan, Mark E.
, p. 4790 - 4798 (2007/10/03)
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 αvβ3 receptor. This compound has an excellent in vitro profile (IC50 = 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.
