Non-peptide αvβ3 antagonists. Part 5: identification of potent RGD mimetics incorporating 2-aryl β-amino acids as aspartic acid replacements

doi:10.1016/S0960-894X(02)00743-6

Bioorganic & Medicinal Chemistry Letters

Volume 12, Issue 23, 2 December 2002, Pages 3483-3486

https://doi.org/10.1016/S0960-894X(02)00743-6 Get rights and content

Abstract

A series of novel, highly potent α_vβ₃ receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl β-amino acids function as potent aspartic acid replacements.

Graphic

Introduction

Osteoporosis is a systemic skeletal disease characterized by low bone mass and associated with an increased risk of fractures.¹ In post-menopausal women, osteoporotic bone loss results from a net increase in the number and activity of bone-resorbing osteoclast cells. The integrin receptor α_vβ₃ is highly expressed in osteoclasts and plays a critical role in both the adhesion and migration of osteoclasts on the bone surface.² Antibodies to α_vβ₃, and more recently non-peptide RGD (arg-gly-asp) mimetics, have been reported to inhibit bone resorption in vitro and prevent bone loss in vivo.³ Our laboratories have been active in the search for non-peptide α_vβ₃ antagonists that could be utilized as novel therapies in the prevention and treatment of osteoporosis.

In a previous communication,⁴ we described a novel, potent class of ‘chain-shortened’ α_vβ₃ antagonists that display favorable pharmacokinetic profiles. We have also reported antagonists to the integrin receptor GPIIbIIIa (also known as α_IIbβ₃),⁵ that also recognizes the RGD tripeptide sequence. A critical potency-enhancing feature identified in an earlier series of GPIIbIIIa antagonists⁶ was the sulfonamide substitiuent alpha to the carboxylic acid terminus. Indeed, α-sulfonamyl α_vβ₃ antagonists were known to be potent inhibitors although oral pharmacokinetic profiles as a whole were poor.⁷ We postulated that α-aryl substituted analogues might also function as potent α_vβ₃ antagonists, while maintaining similar physical properties and pharmacokinetic profiles to their β-aryl counterparts. We examined the 3-aryl versus 2-aryl substitution SAR in the chain-shortened series and in particular for substituted and cyclized tetrahydronaphthyridine analogues (Fig. 1).

Section snippets

Chemistry

The synthesis of specific 2-aryl β-amino esters and the final products are shown in Scheme 1, Scheme 2, Scheme 3, Scheme 4. This chemistry was applied to prepare the other 2-aryl analogues shown in Table 1.

The preferred route for synthesis of the 2-aryl β-amino esters utilized a Mannich-type addition of the lithio enolate of an aryl acetate to benzyloxime of formaldehyde (Scheme 1). Heck coupling of the aryl triflate⁸ 1 with the silyl ketene acetal 2 derived from tert-butyl acetate provided the

Results and discussion

Compounds were evaluated for their ability to inhibit the binding of a high affinity radioligand to human α_vβ₃ immobilized on scintillation proximity beads (SPAV3).¹³ Table 1 depicts a comparison of the IC₅₀ values in this assay for the corresponding 2- and 3-arylsubstituted chain-shortened analogues. With the exception of 1-1B, all of the 3-aryl analogues were tested as the single (S)-enantiomer. The racemic 2-aryl analogues exhibited in vitro potencies that were comparable to or better than

Conclusion

In summary, we have identified a new class of highly potent, non-peptide α_vβ₃ receptor antagonists, with favorable pharmacokinetic profiles, where a 2-aryl β-amino acid functions as a potent aspartic acid replacement. In particular, analogue 1-4A shows improved (3-fold) binding affinity for the α_vβ₃ receptor versus 1-4B, while maintaining a good pharmacokinetic profile. Further improvements in potency were realized in this series through substitution on the tetrahydronaphthyridine moiety,

References (13)

D.C Cole
Tetrahedron
(1994)
(b)Dihydrobenzofuranyl: See ref...J.G Rico et al.
J. Org. Chem.
(1993)
T.B Johnson et al.
J. Am. Chem. Soc.
(1936)
(e)Tetrahydronaphthyridinyl side chains: Tetrahydronaphthyridinyl pentanoic acid: See ref...(f)3-Cyclopropyl: Wang, J.; Whitman, D. B.; Hutchinson, J. H.; Halczenko, W.; Duggan, M. E.; Hartman, G. D.; Leu, C....
J.E Compston
Drugs
(1997)
J.A Kanis et al.
Osteoporosis Int.
(1997)
L.T Duong et al.
Front. Biosci.
(1998)
B.A Crippes et al.
Endocrinology
(1996)
M Yamamoto et al.
Endocrinology
(1998)
M.W Lark et al.
J. Pharm. Exp. Therap.
(1999)
Coleman, P. J.; Askew, B. C.; Hutchinson, J. H.; Whitman, D. B.; Perkins, J. J.; Hartman, G. D.; Rodan, G. A.; Leu, C....
M.E Duggan et al.
J. Med. Chem.
(1995)
B.C Askew et al.
Bioorg. Med. Chem. Lett.
(1996)

There are more references available in the full text version of this article.

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Citation Excerpt :
These results suggest that an orally active, small molecule αvβ3 antagonist may have utility in the treatment of osteoporosis. Previously, several reports from these laboratories described our work toward ‘chain-shortened’ RGD mimetics as potential inhibitors of bone resorption.16,17 The chain-shortened mimetics are potent antagonists that offer significant improvements in pharmacokinetic profiles as compared to their ‘full-length’ analogues.
Antagonists of the integrin receptor α_vβ₃ are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing α_vβ₃ receptor antagonists is described. Two sets of diasteromeric pairs of high-affinity antagonists demonstrated marked differences in log P values, which translated into differing dog pharmacokinetic properties. One member of this set was demonstrated to be effective in reducing bone resorption in rats.

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Non-peptide αvβ3 antagonists. Part 5: identification of potent RGD mimetics incorporating 2-aryl β-amino acids as aspartic acid replacements

Abstract

Introduction

Section snippets

Chemistry

Results and discussion

Conclusion

Tetrahedron

J. Org. Chem.

J. Am. Chem. Soc.

Drugs

Osteoporosis Int.

Front. Biosci.

Endocrinology

Endocrinology

J. Pharm. Exp. Therap.

J. Med. Chem.

Bioorg. Med. Chem. Lett.

Non-peptide α_vβ₃ antagonists. Part 5: identification of potent RGD mimetics incorporating 2-aryl β-amino acids as aspartic acid replacements