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

• Published in: European journal of medicinal chemistry 2015-06, Vol.97, p.1-9
• Main Authors: Wan, Zheng-Yong, Yao, Jin, Tao, Yuan, Mao, Tian-Qi, Wang, Xin-Long, Lu, Yi-Pei, Wang, Hai-Feng, Yin, Hong, Wu, Yan, Chen, Fen-Er, De Clercq, Erik, Daelemans, Dirk, Pannecouque, Christophe
• Format: Article
• Language: English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antiviral agent; Biological activity; Cells, Cultured; DAPY; Drug Discovery; HIV Reverse Transcriptase - antagonists & inhibitors; Humans; Molecular Structure; NNRTI; Piperidine; 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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.04.050

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. [Display omitted] •The etravirine–VRX-480773 hybrids previously disclosed were further optimized.•Novel piperidin-4-yl-aminopyrimidines were designed using molecular hybridization.•26 new compounds were designed and synthesized as the anti-drug resistant HIV NNRTIs.•Most compounds have EC50 at single-digit nanomolar concentrations against WT HIV-1.•SARs were discussed in detail.