The stereoselective targeting of a specific enzyme-substrate complex is the molecular mechanism for the synergic inhibition of HIV-1 reverse transcriptase by (R)-(-)-PPO464 - A novel generation of nonnucleoside inhibitors

The human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse trans criptase (RT) inhibitor pyrrolopyridooxazepinone (PPO) derivative, (+/-)-PP O294, was shown to be active toward wild type and mutated HIV-1 RT and to a ct synergistically in combination with 3'-azido-3'-deoxythymidine (Campiani , G., Morelli, E., Fabbrini, M., Nacci, V., Greco, G., Novellino, E., Ramun no, A., Maga, G., Spadari, S., Caliendo, G., Bergamini, A., Faggioli, E., U ccella, I., Bolacchi, F., Marini, S., (1999) J. Med. Chant. 42, 4462-4470). The (+/-)-PPO294 racemate was resolved into its pure enantiomers, and the absolute configuration was determined by x-ray analysis. Only one enantiome r, (R)-(-)-PPO464, displayed antiviral activity against both the wild type and the K103N mutant HIV-1 RT and was found to interact exclusively with th e reaction intermediate formed by RT complexed with both the DNA and the nu cleotide substrates. Being the first compound of its class to display this behavior, (R)-(-)-PPO464 is the representative of a novel generation of non nucleoside inhibitors. (R)(-)-PPO464 showed significant synergism when test ed in combination with other RT inhibitors and efficiently inhibited viral replication when tested against the laboratory strain HIV-1 IIIB or against either wild type or multidrug-resistant clinical isolates. Pharmacokinetic studies in mice and rats showed a more favorable profile for (R)-(-)-PPO46 4 than for the corresponding racemate. (R)-(-)-PPO464 was also found to eas ily cross the blood-brain barrier. The coadministration of the HIV-1 protea se inhibitor ritonavir increased the bioavailability of (R)-(-)-PPO464, hav ing little effect on its plasma and brain elimination rates.