304   TMC120 (R147681), a Next-Generation NNRTI, Has Potent In Vitro Activity Against NNRTI-Resistant HIV Variants.

M. P. De Bethune*¹, K. Andries², D. Ludovici³, P. Lewi⁴, H. Azijn¹, M. De Jonge⁴, J. Heeres⁴, M. Kukla³, P. Janssen⁴, and R. Pauwels¹.
¹Tibotec, Mechelen, Belgium;²Janssen Res. Fndn., Beerse, Belgium;³Janssen Res. Fndn., Spring House, PA; and⁴Janssen Res. Fndn., Vosselaar, Belgium.

Background:Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent antiretrovirals but extensive cross-resistance is observed among approved inhibitors of this class. The next generation of NNRTIs should have potent activity against variants resistant to NNRTIs currently in use.

Methods:Lead compound optimization was accomplished by parallel, rather than 'sequential, screening of derivatives against wild-type and NNRTI-resistant strains with clinically important mutations. Lead optimization also included assessment of metabolic stability (incubation with human liver microsomes [HLM]) and the influence of human serum proteins on anti-HIV potency.

Results:TMC120 (R147681), a dianilinopyrimidine derivative, was selected from >300 triazine and pyrimidine analogues of the lead compound. Its anti-HIV activity profile is shown in the table. The potency of TMC120 is not influenced byα;₁-acid glycoprotein and moderately affected by human serum albumin (20-fold increase of IC₅₀). Two-hour incubation of TMC120 with HLM resulted in+30% degradation.

Conclusion:TMC120 (R147681) has a favorable in vitro activity profile against NNRTI resistant variants. This activity, combined with encouraging safety and pharmacokinetic profiles, has led to Phase II testing of TMC120 in NNRTI-naive and -experienced patients.