Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro1,8naphthyridine group as a ...potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
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-tetrahydro1,8naphthyridine 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.
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