Nonpeptide αvβ3 Antagonists. 1. Transformation of a Potent, Integrin-Selective αIIbβ3 Antagonist into a Potent αvβ3 Antagonist

Modification of the potent fibrinogen receptor (αIIbβ3) antagonist 1 generated compounds with high affinity for the vitronectin receptor αvβ3. 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 αvβ3. 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 αvβ3 is also reported.