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.
Zheng-Yong Wan  1 ,  Jin Yao  1 ,  Yuan Tao  1 ,  Tian-Qi Mao  2 ,  Xin-Long Wang  1 ,  Yi-Pei Lu  1 ,  Hai-Feng Wang  1 ,  Hong Yin  1 ,  Yan Wu  3 ,  Fen-Er Chen  4 ,  Erik De Clercq  5 ,  Dirk Daelemans  5 ,  Christophe Pannecouque  5
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: [email protected].
  • 4. Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China. Electronic address: [email protected].
  • 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.