Authors: Chen, Xuwang; Zhan, Peng; Li, Dongyue; De Clercq, Erik; Liu, Xinyong

Source: Current Medicinal Chemistry, Volume 18, Number 3, January 2011 , pp. 359-376(18)

Publisher: Bentham Science Publishers

Abstract:

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent most promising anti- AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). They have a unique antiviral potency, high specificity and low cytotoxicity. However, to a great extent, the efficacy of HIV-1 NNRTIs is compounded by rapid emergence of drug resistant virus strains, which calls for continuous efforts to develop novel HIV-1 NNRTIs. Diarylpyrimidine (DAPY) derivatives, one family of NNRTIs with superior activity profiles against wild-type HIV-1 and mutant strains, have attracted considerable attention over the past few years. Among the potent lead DAPY compounds, etravirine was approved by FDA in January 2008, and its analogue rilpivirine (TMC278) has advanced to phase III clinical trials. The successful development of DAPYs results from a multidisciplinary approach involving traditional medicinal chemistry, structural biology, crystallography and computational chemistry. Recently, a number of novel characteristics of DAPYs including conformational flexibility, positional adaptability, key hydrogen bonds and specifically targeting conserved residues of RT, have been identified, providing valuable avenues for further optimization and development of new DAPY analogues as promising anti-HIV drug candidates.

In this review, we first present a brief historical account of the medicinal chemistry of the DAPY NNRTIs, then focus on the extensive structural modifications, SAR studies, and binding mode analysis based on crystallographic and molecular modeling. Other structural related NNRTI scaffolds will also be reviewed.

Keywords: HIV-1; NNRTIs; DAPY; TMC125; TMC278; drug design; drug-resistance; Acquired immune deficiency syndrome (AIDS); vaccine; deaths; pandemic diseases; highly ac-tive antiretroviral therapy (HAART); cytotoxicity; nucleoside re-verse transcriptase inhibitors (NRTI; potency; pharmacokinetic; pharmacokinetic; di-arylpyrimidine; ligand binding; crystallography; computa-tional chemistry; DAPY NNRTIS; aryl groups; imidoyl thiourea; vaginal HIV microbicide; X-ray crystallographic; torsional flexibility; potency; pyrazinones; Free energy perturbation

Document Type: Research article

DOI: http://dx.doi.org/10.2174/092986711794839142

Publication date: 2011-01-01

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• Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.

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