Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates

Abstract

The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.

Crystal Structures of HIV-1 Reverse Transcriptases Mutated at Codons 100, 106 and 108 and Mechanisms of Resistance to Non-nucleoside Inhibitors

“…13,28,30 For Val108Ile: nevirapine (tenfold). 27,28,31 We are undertaking systematic studies of the structures of HIV-1 RTs containing mutations that give resistance to NNRTIs in order to allow further understanding of mechanisms of drug resistance. Such information should be of value in the design of new drugs to combat infection by drug resistant HIV.…”

Vaginal microbicides and the prevention of HIV transmission

“…Two non-nucleoside reverse transcriptase inhibitors (NNRTIs), TMC120 and UC781, have proceeded to preclinical or clinical testing as potential topical microbicides and have several features in common: unlike first-generation NNRTIs that only require one mutation before viral resistance occurs, TMC120 and UC781 usually require at least two mutations 149–151. Both compounds show minimal systemic absorption, and both had good safety profiles in animal studies 152,153.…”

A thermodynamic study of the cyclodextrin-UC781 inclusion complex using a HPLC method

“…1), is a tight-binding HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) that is an extremely potent inhibitor of HIV-1 in cell culture [10–12]. It belongs to the class of (thio)carboxanilide derivatives, the prototype of which (UC84) was originally reported as an antiviral agent by Bader et al [13].…”

“…Furthermore, UC781 targets HIV-1 RT and is effective against a variety of NNRTI resistant HIV-1 strains. Importantly, high resistance to UC781 is only obtained when more than one mutation occurs in the NNRTI binding pocket [12]. However, the extremely high hydrophobicity and low solubility (<30 ng/mL) of UC781 poses a huge challenge in formulation development of UC781.…”