Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses
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...
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| Published in: | Bioorganic & medicinal chemistry letters Vol. 20; no. 14; pp. 4215 - 4218 |
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| Main Authors: | , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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15-07-2010
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| Abstract | 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. |
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| AbstractList | 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 K103 N/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. 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. |
| Author | Heilek, Gabrielle M. Dunten, Pete W. Klumpp, Klaus Gleason, Shelley Yang, Minmin Wang, Zhanguo Hirschfeld, Donald R. Qiu, Zongxing Villaseñor, Armando G. Harris, Seth F. Kertesz, Denis J. Brotherton-Pleiss, Christine Lin, Xianfeng Mirzadegan, Taraneh Hang, Julie Qi |
| Author_xml | – sequence: 1 givenname: Denis J. surname: Kertesz fullname: Kertesz, Denis J. email: deniskertesz@comcast.net organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 2 givenname: Christine surname: Brotherton-Pleiss fullname: Brotherton-Pleiss, Christine organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 3 givenname: Minmin surname: Yang fullname: Yang, Minmin organization: Roche R&D Center (China), Shanghai 201203, China – sequence: 4 givenname: Zhanguo surname: Wang fullname: Wang, Zhanguo organization: Roche R&D Center (China), Shanghai 201203, China – sequence: 5 givenname: Xianfeng surname: Lin fullname: Lin, Xianfeng organization: Roche R&D Center (China), Shanghai 201203, China – sequence: 6 givenname: Zongxing surname: Qiu fullname: Qiu, Zongxing organization: Roche R&D Center (China), Shanghai 201203, China – sequence: 7 givenname: Donald R. surname: Hirschfeld fullname: Hirschfeld, Donald R. organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 8 givenname: Shelley surname: Gleason fullname: Gleason, Shelley organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 9 givenname: Taraneh surname: Mirzadegan fullname: Mirzadegan, Taraneh organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 10 givenname: Pete W. surname: Dunten fullname: Dunten, Pete W. organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 11 givenname: Seth F. surname: Harris fullname: Harris, Seth F. organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 12 givenname: Armando G. surname: Villaseñor fullname: Villaseñor, Armando G. organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 13 givenname: Julie Qi surname: Hang fullname: Hang, Julie Qi organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 14 givenname: Gabrielle M. surname: Heilek fullname: Heilek, Gabrielle M. organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA – sequence: 15 givenname: Klaus surname: Klumpp fullname: Klumpp, Klaus organization: Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA |
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| Keywords | 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 |
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| SubjectTerms | 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 |
| Title | Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-Benzyl derivatives with broad potency against resistant mutant viruses |
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