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Article pubs.acs.org/jmc

Difluoromethylbenzoxazole Pyrimidine Thioether Derivatives: A Novel Class of Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors†
Jérémie Boyer,‡ Eric Arnoult,§ Maurice Médebielle,*,‡ Jérôme Guillemont,*,§ Johan Unge,*,∥ and Dirk Jochmans⊥,#
‡

Université de Lyon, Université Claude Bernard Lyon 1, Institut de Chimie et Biochimie Moléculaires etSupramoléculaires (ICBMS), UMR CNRS-UCBL-INSA, Equipe “Synthèse de Molécules d’Intérêt Thérapeutique (SMITH)”, Bâtiment Curien, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France § Chemistry Lead Antimicrobial Research, Janssen-Cilag/Tibotec, Campus de Maigremont BP615, F-27106 Val de Reuil Cedex, France ∥ MAX-lab, Lund University, P.O. Box 118, SE-221 00 Lund, Sweden ⊥ Tibotec-Virco BVBA, ADivision of Janssen Pharmaceutical Companies of Johnson & Johnson, Turnhoutseweg 30, BE-2340 Beerse, Belgium
S * Supporting Information

ABSTRACT: This paper reports the synthesis and antiviral properties of new difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors. By use of a combination of structural biology study andtraditional medicinal chemistry, several members of this novel class were synthesized using a single electron transfer chain process (radical nucleophilic substitution, SRN1) and were found to be potent against wild-type HIV-1 reverse transcriptase, with low cytotoxicity but with moderate activity against drug-resistant strains. The most promising compound 24 showed a significant EC50 value close to 6.4 nMagainst HIV-1 IIIB, a moderate EC 50 value close to 54 μM against an NNRTI resistant double mutant (K103N + Y181C), but an excellent selectivity index >15477 (CC 50 > 100 μM).

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INTRODUCTION

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been shown to be a key component of highly active antiretroviral therapy (HAART). The use of NNRTIs has become part of standardcombination antiviral therapies producing very effective drugs with clinical efficacy comparable to that of other antiviral regimens. There is, however, a critical issue with the emergence of drug-resistant HIV-1 mutants, and a need has arisen for novel NNRTIs with improved activity profiles. There are currently three commercially available first generation NNRTIs: efavirenz, nevirapine, and delavirdine(Figure 1).1 Recently, the second generation NNRTI etravirine (TMC125, Figure 1), a diarylpyrimidine (DAPY) derivative, has been approved by the FDA and has demonstrated activity toward a number of clinically observed mutations.2 Further research to develop an even better DAPY derivative has led to the discovery of an advanced NNRTI, rilpivirine (TMC-278, Figure 1), which has been approved by the FDAin February 2011 and showed better potency and pharmacological profiles than etravirine.2 Quite close analogues of the DAPY family, such as diarylpyridine 1,3 diarylanilines 2 and 3,3 and pyrrolopyrimi© 2011 American Chemical Society

dines 4 (RDEA-640) and 5 (RDEA-427, preclinical),4 have been recently disclosed and displayed similar or better potency than etravirine (Figure SI-1 of SupportingInformation). Additional structures have been disclosed from major pharmaceutical companies, and some of them are already in clinical trials such as trisubstituted thioacetanilinide triazole 6 (RDEA-806, phase II),4 arylphosphoindole derivative 7 (IDX899/GSK-2248761, phase II),5 diaryl ether/pyrazolo[3,4-b]pyridine 8 (MK-4965, phase I) (Figure SI-1 of Supporting Information).6 Compound 9(L-696,229)7 and some analogues (10 and 11) are potent NNRTIs (Figure SI-2 of Supporting Information) and were discovered in a screening program at Merck. Although their clinical development was suspended because of the emergence of resistance, the pyridine-2(1H)ones remained an attractive pharmacophore and various synthetic programs were initiated in order to discover new molecules that could...