Nonpeptide α_vβ₃ Antagonists. 8. In Vitro and in Vivo Evaluation of a Potent α_vβ₃ Antagonist for the Prevention and Treatment of Osteoporosis

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.

The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration

“…In addition to reduced osteoblastic differentiation, it is possible that presentation of α V β 3 -selective ligands reduces overall bone formation by enhancing osteoclastic activity. Integrin α V β 3 is a major component of podosomes in the sealing zones of resorptive pits [32], and α V β 3 antagonists reduce bone resorption by reducing osteoclast activity [33][34][35]. However, we did not observe accumulation of multi-nucleated cells at the bone tissue-implant interface, suggesting that osteoclastic responses were not the dominant mechanism.…”

Integrin αvβ3-targeted gold nanoshells augment tumor vasculature-specific imaging and therapy

“…In addition to RGD peptides, some research groups have synthesized small molecule antagonists based on RGD motifs to achieve comparable affinity with integrin α v β 3 . [27][28][29] In this study we compared the binding affinities to integrin α v β 3 of the cyclo(RGDfK) (cyclo(Arg-Gly-Asp-D-Phe-Lys)) peptide and the synthesized antagonist 4-[2- (3,4,5,6- Figure 1B) 27 and their NS conjugates by three different (ELISAs). The binding specificity of NSRGDfK to integrin α v β 3 -expressing U87 tumor cells was then validated by silver staining assays.…”

IN VITRO AND IN VIVO METABOLISM OF A POTENT AND SELECTIVE INTEGRIN αvβ3 ANTAGONIST IN RATS, DOGS, AND MONKEYS

“…Compound A, 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrindin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid (Fig. 1), a potent and selective antagonist of integrin ␣ v ␤ 3 receptor, is currently under evaluation as a possible treatment for osteoporosis (Hutchinson et al, 2003;Prueksaritanont et al, 2004).Metabolism studies of drug candidates have become an integral part of the drug discovery and development process (Lin et al, 2003;Roberts, 2003). Results generated from these studies have been commonly used in designing chemicals that are metabolically more stable and often with better pharmacokinetic properties.…”

“…Compound A, 3-{2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrindin-2-yl)propyl]-imidazolidin-1-yl}-3(S)-(6-methoxy-pyridin-3-yl)propionic acid ( Fig. 1), a potent and selective antagonist of integrin ␣ v ␤ 3 receptor, is currently under evaluation as a possible treatment for osteoporosis (Hutchinson et al, 2003;Prueksaritanont et al, 2004).…”

“…It has a specific activity of 31.0 Ci/mg and a radiochemical purity Ͼ98% as determined by radio-HPLC. Authentic standards of A, metabolites M1 (O-desmethyl-A), M3c (7-hydroxytetrahydronaphthyridin-A), M6b (7-oxo-tetrahydronaphthyridin-A), M7 (naphthyridine derivative of A), and M8 (acyl glucuronide of A) were prepared as described previously (Hutchinson et al, 2003). Animal Studies.…”