CHARACTERIZATION OF THE ANTIVIRAL ACTIVITY OF HIGHLY SUBSTITUTED PYRROLES - A NOVEL CLASS OF NONNUCLEOSIDE HIV-1 REVERSE-TRANSCRIPTASE INHIBITOR

As a result of mass screening of the Parke-Davis Pharmaceutical compound library for inhibitors of HIV-1 reverse transcriptase (RT) activity, a novel class of inhibitor, the pyrroles, was identified, Subsequently, a series of analogues was screened for inhibitory activity against HIV-1 and some structure-activity relationships were identified. Further characterization of the most potent pyrrole involved comparing its effects in peripheral blood ampholytes (PBLs) with its effects in transformed cell lines; the pyrrole had the same efficacy (EC(50) = approximately 2 mu M) but was less toxic in PBLs (IC50 = 175 mu M) than in the cell lines CEM-SS and MT-2 (IC50 = 60-70 mu M). The pyrrole was active against a strain of HIV-1 resistant to AZT (strain G9106) but lost activity against both HIV-2 (strain ROD) and a strain of HIV-1 resistant to a non-nucleoside reverse transcriptase inhibitor (the pyridinone-resistant strain A17). Moreover, in direct enzymatic testing against HIV-1 RT purified from virus particles and against RT expressed recombinantly, the pyrrole showed potent inhibitory activity. We conclude that the pyrroles present a novel class of HIV-1 non-nucleoside reverse transcriptase inhibitor.