Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Zheng-Yong Wan; Jin Yao; Yuan Tao; Tian-Qi Mao; Xin-Long Wang; Yi-Pei Lu; Hai-Feng Wang; Hong Yin; Yan Wu; Fen-Er Chen; Erik De Clercq; Dirk Daelemans; Christophe Pannecouque

doi:10.1016/j.ejmech.2015.04.050

Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors

Eur J Med Chem. 2015 Jun 5:97:1-9. doi: 10.1016/j.ejmech.2015.04.050. Epub 2015 Apr 27.

Authors

Zheng-Yong Wan¹, Jin Yao¹, Yuan Tao¹, Tian-Qi Mao², Xin-Long Wang¹, Yi-Pei Lu¹, Hai-Feng Wang¹, Hong Yin¹, Yan Wu³, Fen-Er Chen⁴, Erik De Clercq⁵, Dirk Daelemans⁵, Christophe Pannecouque⁵

Affiliations

¹ Department of Chemistry, Fudan University, Shanghai 200433, PR China.
² Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China.
³ Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: wywin8@163.com.
⁴ Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China. Electronic address: rfchen@fudan.edu.cn.
⁵ Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.

PMID: 25935383
DOI: 10.1016/j.ejmech.2015.04.050

Abstract

A novel series of piperidin-4-yl-aminopyrimidine derivatives were designed fusing the pharmacophore templates of etravirine-VRX-480773 hybrids our group previously described and piperidine-linked aminopyrimidines. Most compounds displayed significantly improved activity against wild-type HIV-1 with EC50 values in single-digit nanomolar concentrations compared to etravirine-VRX-480773 hybrids. Selected compounds were also evaluated for activity against reverse transcriptase, and had lower IC50 values than that of nevirapine. The improved potency observed in this in vitro model of HIV RNA replication partly validates the mechanism by which this class of allosteric pyrimidine derivatives inhibits reverse transcriptase, and represents a remarkable step forward in the development of AIDS therapeutics.

Keywords: Antiviral agent; Biological activity; DAPY; NNRTI; Piperidine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology
Cells, Cultured
Drug Discovery*
HIV Reverse Transcriptase / antagonists & inhibitors*
Humans
Molecular Structure
Nitriles
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Pyridazines / chemistry
Pyridazines / pharmacology
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Reverse Transcriptase Inhibitors / chemical synthesis*
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Anti-HIV Agents
Nitriles
Piperidines
Pyridazines
Pyrimidines
Reverse Transcriptase Inhibitors
etravirine
piperidine
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
pyrimidine