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Background:  NNRTI therapy has become a key component of HAART for the treatment of HIV infection.  However, increasing resistance to currently marketed NNRTIs has been reported in clinical studies. The goal of this work was to identify agents that maintain potency against a range of clinically relevant mutated viruses while maintaining in vivo characteristics suitable for once-daily administration.

Methods:  A series of 5,10-dihydrobenzo[b][1,8]napthyridine N-oxides was synthesized and optimized for potency against WT virus and a panel of clinically relevant single and double mutant isolates of HIV-1. Serum protein binding and in vivo pharmacokinetic properties were assessed for compounds that met target potency criteria.

Results:  Substituent-group optimization led to a series of compounds with potent antiviral activity against a panel of HIV-1 variants.   The 7-fluoro-5-cyclopropylmethyloxy-5-trifluoromethyl derivative with antiviral IC90s of 4.2 nM, 42, nM and 17 nM against wt, K103N/L100I and K103N/Y181C, respectively, an unbound fraction in human serum of 7.8%, and excellent animal pharmacokinetics was advanced into Phase I clinical trials with a target trough concentration of 410 nM.  Development of this candidate was discontinued in response to adverse cardiovascular events in the clinic.

 Conclusions:  Medicinal optimization of a series of tricyclic NNRTIs led to the identification compounds with improved activity profiles against clinically relevant HIV mutant variants relative to currently marketed NNRTIs at clinically achievable concentrations.

Keywords: NNRTI