DISCOVERY OF RITONAVIR, A POTENT INHIBITOR OF HIV PROTEASE WITH HIGH ORAL BIOAVAILABILITY AND CLINICAL EFFICACY

The structure-activity studies leading to the potent and clinically ef ficacious HIV protease inhibitor ritonavir are described. Beginning wi th the moderately potent and orally bioavailable inhibitor A-80987, sy stematic investigation of peripheral (P3 and P2') heterocyclic groups designed to decrease the rate of hepatic metabolism provided analogues with improved pharmacokinetic properties after oral dosing in rats. R eplacement of pyridyl groups with thiazoles provided increased chemica l stability toward oxidation while maintaining sufficient aqueous solu bility for oral absorption, Optimization of hydrophobic interactions w ith the HIV protease active site produced ritonavir, with excellent in vitro potency (EC50 = 0.02 mu M) and high and sustained plasma concen trations after oral administration in four species. Details of the dis covery and preclinical development of ritonavir are described.