Molecular modeling, synthesis, and activity studies of novel biaryl and fused-ring BACE1 inhibitors

Srinivas Reddy Chirapu, Boobalan Pachaiyappan, Hikmet F. Nural, Xin Cheng, Hongbin Yuan, David C. Lankin, Samer O. Abdul-Hay, Gregory R.J. Thatcher, Yong Shen, Alan P. Kozikowski, Pavel A. Petukhov

Research output: Contribution to journalArticlepeer-review

Abstract

A series of transition state analogues of beta-secretases 1 and 2 (BACE1, 2) inhibitors containing fused-ring or biaryl moieties were designed computationally to probe the S2 pocket, synthesized, and tested for BACE1 and BACE2 inhibitory activity. It has been shown that unlike the biaryl analogs, the fused-ring moiety is successfully accommodated in the BACE1 binding site resulting in the ligands with excellent inhibitory activity. Ligand 5b reduced 65% of Aβ40 production in N2a cells stably transfected with Swedish human APP.

Original languageEnglish (US)
Pages (from-to)264-274
Number of pages11
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2009

Keywords

  • Alzheimer
  • Aspartic protease
  • BACE1
  • Computer-aided molecular design

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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