Discovery of piperidin-4-yl-aminopyrimidine derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors.
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.
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Zheng-Yong
ZY
Wan
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Jin
J
Yao
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Yuan
Y
Tao
Department of Chemistry, Fudan University, Shanghai 200433, PR China; Institute of Biomedical Science, Fudan University, Shanghai 200433, PR China.
Tian-Qi
TQ
Mao
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Xin-Long
XL
Wang
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Yi-Pei
YP
Lu
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Hai-Feng
HF
Wang
Department of Chemistry, Fudan University, Shanghai 200433, PR China.
Hong
H
Yin
Department of Chemistry, Fudan University, Shanghai 200433, PR China. Electronic address: wywin8@163.com.
Yan
Y
Wu
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.
Fen-Er
FE
Chen
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Erik
E
De Clercq
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Dirk
D
Daelemans
Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.
Christophe
C
Pannecouque
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D055808:Drug Discovery; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009570:Nitriles; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D009570:Nitriles; D010880:Piperidines; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C032727:piperidine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C030986:pyrimidine
Antiviral agent; Biological activity; DAPY; NNRTI; Piperidine