Structure-Based Discovery of Novel NH 2 -Biphenyl-Diarylpyrimidines as Potent Non-Nucleoside Reverse Transcriptase Inhibitors with Significantly Improved Safety: From NH 2 -Naphthyl-Diarylpyrimidine to NH 2 -Biphenyl-Diarylpyrimidine.

Autor: Jin X; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, P. R. China., Zhao LM; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, P. R. China., Wang S; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China., Huang WJ; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China., Zhang YX; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China., Pannecouque C; Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium., De Clercq E; Rega Institute for Medical Research, KU Leuven, Herestraat 49, B-3000 Leuven, Belgium., Chen FE; Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China.; Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China.; Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, Yanji 133002, P. R. China.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Jun 23; Vol. 65 (12), pp. 8478-8492. Date of Electronic Publication: 2022 Jun 01.
DOI: 10.1021/acs.jmedchem.2c00468
Abstrakt: Results from recently completed studies suggested that the NH 2 -naphthyl-diarylpyrimidine JX-7 displayed remarkable inhibitory activity against wild-type HIV-1 (EC 50 = 5 nM) and numerous clinically observed variants in MT-4 cells; however, its high cytotoxicity (CC 50 = 19 μM) precluded its further development as a clinical candidate. One approach we took to improve the safety involved replacing the naphthyl of JX-7 with biphenyl to provide a series of novel NH 2 -biphenyl-DAPYs. Investigation of the structure-activity relationships (SARs) led to the identification of 4ab , a potent NNRTI with significantly reduced cytotoxicity (CC 50 = 120 μM), approximately 6-fold lower than JX-7 , which maintained remarkable anti-HIV-1 activity against wild-type HIV-1 (EC 50 = 1.9 nM) and multiple mutant strains simultaneously. Also, 4ab displayed weak CYP sensitivity, little inhibition of hERG, and no apparent in vivo acute toxicity. These promising results demonstrate that 4ab can be used as a drug candidate for HIV-1 therapy.
Databáze: MEDLINE
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