Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 14; pp. 4215 - 4218
• Main Authors: Kertesz, Denis J., Brotherton-Pleiss, Christine, Yang, Minmin, Wang, Zhanguo, Lin, Xianfeng, Qiu, Zongxing, Hirschfeld, Donald R., Gleason, Shelley, Mirzadegan, Taraneh, Dunten, Pete W., Harris, Seth F., Villaseñor, Armando G., Hang, Julie Qi, Heilek, Gabrielle M., Klumpp, Klaus
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-07-2010; Elsevier
• Subjects: Aminopyrimidine; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral; Antiviral agents; Biological and medical sciences; Crystal structure; Drug Discovery; Drug Resistance, Viral - genetics; HIV; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Inhibitor; Medical sciences; Models, Molecular; Mutation; NNRTI; Pharmacology. Drug treatments; Pyrimidines - chemistry; Pyrimidines - pharmacology; Reverse transcriptase; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Viral mutants; Aminopyrimidine; Reverse transcriptase; HIV; NNRTI; Antiviral; Inhibitor; Viral mutants; Nitrile; RNA-directed DNA polymerase; Sulfone; HIV-1 virus; Non nucleoside compound; Structure activity relation; Chlorine Organic compounds; Reverse transcriptase inhibitor; Piperidine derivatives; Bromine Organic compounds; Enzyme; Transferases; Benzene derivatives; Retroviridae; Enzyme inhibitor; Lentivirus; In vitro; Virus; Resistance; Nucleotidyltransferases; Pyrimidine derivatives; Human immunodeficiency virus; Mutation
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.05.040

An analysis of the binding motifs of known HIV-1 non-nucleoside reverse transcriptase inhibitors has led to discovery of novel piperidine-linked aminopyrimidine derivatives with broad activity against wild-type as well as drug-resistant mutant viruses. Notably, the series retains potency against the K103N/Y181C and Y188L mutants, among others. Thus, the N-benzyl compound 5k has a particularly attractive profile. Synthesis and SAR are presented and discussed, as well as crystal structures relating to the binding motifs.