Nonpeptide alpha(v)beta(3) antagonists. 1. Transformation of a potent, integrin-selective alpha(IIb)beta(3) antagonist into a potent alpha(v)beta(3) antagonist |
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| Authors: | Duggan M E Duong L T Fisher J E Hamill T G Hoffman W F Huff J R Ihle N C Leu C T Nagy R M Perkins J J Rodan S B Wesolowski G Whitman D B Zartman A E Rodan G A Hartman G D |
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| Affiliation: | Departments of Medicinal Chemistry, Bone Biology and Osteoporosis Research, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. |
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| Abstract: | Modification of the potent fibrinogen receptor (alpha(IIb)beta(3)) antagonist 1 generated compounds with high affinity for the vitronectin receptor alpha(v)beta(3). Sequential modification of the basic N-terminus of 1 led to the identification of the 5,6,7, 8-tetrahydro[1,8]naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor alpha(v)beta(3). The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to alpha(v)beta(3) is also reported. |
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