Discovery of piperidin-4-yl-aminopyrimidines as HIV-1 reverse transcriptase inhibitors. N-benzyl derivatives with broad potency against resistant mutant viruses

  • Bioorg Med Chem Lett. 2010 Jul 15;20(14):4215-8. doi: 10.1016/j.bmcl.2010.05.040.
Denis J Kertesz  1 ,  Christine Brotherton-Pleiss ,  Minmin Yang ,  Zhanguo Wang ,  Xianfeng Lin ,  Zongxing Qiu ,  Donald R Hirschfeld ,  Shelley Gleason ,  Taraneh Mirzadegan ,  Pete W Dunten ,  Seth F Harris ,  Armando G Villaseñor ,  Julie Qi Hang ,  Gabrielle M Heilek ,  Klaus Klumpp
Affiliations
  • 1. Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. [email protected]
PMID: 20538456 DOI: 10.1016/j.bmcl.2010.05.040
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.