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.
Subject(s)
Naphthyridines/chemical synthesis , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Propionates/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Bone Resorption/pathology , Cell Line , Culture Techniques , Humans , Ligands , Naphthyridines/chemistry , Naphthyridines/pharmacology , Platelet Aggregation/drug effects , Propionates/chemistry , Propionates/pharmacology , Rats , Rats, Sprague-Dawley , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A new series of potent, linearly-minimized, orally active, selective GPIIb/IIIa inhibitors is identified. Thus 15 (L-750,034) achieves interaction via a constrained, non-turned conformation that maintains the proper distance between its charged termini and full sulfonamide exosite interaction. The diminutive stature and the proposed linear conformation of L-750,034 define a new paradigm for the conceptualization of RGD mimics.
