Non-peptide αvβ3 antagonists: Identification of potent, chain-shortened RGD mimetics that incorporate a central pyrrolidinone constraint

Antagonists of the integrin receptor αvβ3 are expected to have utility in the treatment of osteoporosis through inhibition of bone resorption. A series of potent, chain-shortened, pyrrolidinone-containing αvβ3 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.