title: In vitro and in vivo activities of AIC292, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor.
abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important and frequently used elements of highly active antiretroviral therapy (HAART) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. However, the development of drug resistance, as well as the side effects of existing drugs, defines a medical need for novel NNRTIs with excellent tolerability, improved activity against NNRTI-resistant viruses, and a low barrier to resistance. Within the chemical class of diarylpyrazole-[imidazolidinone]-carboxamides, AIC292 was identified as a promising novel HIV-1 NNRTI and has successfully completed single-dose clinical phase I studies. Here, we report on the antiviral activity of AIC292, evaluated in vitro against wild-type and NNRTI-resistant HIV-1 isolates and in vivo using an engineered mouse xenograft model. AIC292 inhibited wild-type HIV-1 laboratory strains at low nanomolar concentrations, was well tolerated in different cell lines, and showed excellent selectivity in a lead profiling screen. In addition, activity of AIC292 could be demonstrated against a broad panel of wild-type HIV-1 group M and group O clinical isolates. AIC292 also retained activity against viruses harboring NNRTI resistance-associated mutations (RAMs), including the most prevalent variants, K103N, Y181C, and G190A. Interestingly, viruses bearing the L100I RAM were hypersusceptible to AIC292. Two-drug combination assays showed no antagonistic interactions between AIC292 and representative marketed HIV drugs with regard to antiviral activity. Furthermore, AIC292 displayed potent antiviral in vivo efficacy in a mouse xenograft model when applied once daily. Taken together, these data show that AIC292 represents a molecule with the antiviral properties of a novel NNRTI for the treatment of HIV-1 infection.
authors: AiCuris GmbH & Co. KG, Wuppertal, Germany.
authors: Steffen
authors: S
authors: Wildum
authors: Daniela
authors: D
authors: Paulsen
authors: Kai
authors: K
authors: Thede
authors: Helga
authors: H
authors: Ruebsamen-Schaeff
authors: Holger
authors: H
authors: Zimmermann
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D017321:Clinical Trials, Phase I as Topic; D024882:Drug Resistance, Viral / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D064593:Heterografts / Q000187:drug effects / Q000821:virology; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: C588299:1-(1-(3-chloro-4-fluorophenyl)-5-(3-chloro-5-fluorophenyl)-1H-pyrazole-3-carbonyl)imidazolidin-4-one; D019380:Anti-HIV Agents; D048289:Imidazolidines; D011720:Pyrazoles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase
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