Structure−Activity Relationship Studies of Novel Benzophenones Leading to the Discovery of a Potent, Next Generation HIV Nonnucleoside Reverse Transcriptase Inhibitor

Abstract

Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC(50) values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies.

Structural Basis for the Improved Drug Resistance Profile of New Generation Benzophenone Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors

“…40 Benzopheneone NNRTIs 1, 2, 3, and the latter's prodrug 4 were synthesized and characterized as reported in earlier papers. [23][24][25][26] Anti-HIV-1 Activity and Resistance Profile of 1 in Cell Culture Systems. The anti-HIV-1 activity of the prototype benzophenone 1 was tested against a wider panel of mutant viruses than previously reported 23 using the methods described in earlier studies.…”

Discovery of Novel Inhibitors of HIV‐1 Reverse Transcriptase Through Virtual Screening of Experimental and Theoretical Ensembles

“…More recently, difluoromethylbenzoxazole (DFMB) pyrimidine thioether derivatives were described that are potent inhibitors of wild‐type RT and are moderately active against various mutants . NSC366102 contains a benzophenone, and compounds in this class can be potent and effective against a variety of RT mutants . To the best of our knowledge, neither the pyrimidinone thoiether nor the benzophenone reported in this paper has been described previously as RT inhibitors.…”

Structural modification of diarylpyrimidine derivatives as HIV-1 reverse transcriptase inhibitors

“…NNRTIs, known as one of the indispensable components of highly active antiretroviral therapy (HAART), have received wide attention due to their unique antiviral potency, high specificity and low cytotoxicity (De Clercq, 2001;Chen et al, 2011). However, the rapid emergence of drug resistance and serious side effects of long term clinical drugs impelled medicinal chemists to develop diverse structures of NNRTIs, such as benzophenones (Chan et al, 2004;Romines et al, 2006), diaryl ethers (Sweeney et al, 2009;Gu et al, 2011b), 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymines (HEPTs) (Meng et al, 2003;Ji et al, 2006), dihydroalkoxybenzyl-oxopyrimidines (DABOs) (Radi et al, 2008;Wang et al, 2008), diaryltriazines (DATAs) (Ludovici et al, 2001b;Xiong et al, 2008), and diarylpyrimidines (DAPYs, Fig. 1) (Ludovici et al, 2001a;Zeng et al, 2010;Rotili et al, 2011).…”