VIRACEPT (NELFINAVIR MESYLATE, AG1343) - A POTENT, ORALLY BIOAVAILABLE INHIBITOR OF HIV-1 PROTEASE

Using a combination of iterative structure-based design and an analysi s of oral pharmacokinetics and antiviral activity, AG1343 (Viracept, n elfinavir mesylate), a nonpeptidic inhibitor of HIV-1 protease, was id entified. AG1343 is a potent enzyme inhibitor (K-i = 2 nM) and antivir al agent (HIV-1 ED50 = 14 nM). An X-ray cocrystal structure of the enz yme-AG1343 complex reveals how the novel thiophenyl ether and phenol-a mide substituents of the inhibitor interact with the S1 and S2 subsite s of HIV-1 protease, respectively. In vivo studies indicate that AG134 3 is well absorbed orally in a variety of species and possesses favora ble pharmacokinetic properties in humans. AG1343 (Viracept) has recent ly been approved for marketing for the treatment of AIDS.