A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors

  • Bioorg Med Chem Lett. 2013 Feb 1;23(3):850-3. doi: 10.1016/j.bmcl.2012.11.054.
Wen-Lian Wu  1 ,  Thavalakulamgara K Sasikumar ,  Martin S Domalski ,  Li Qiang ,  Duane A Burnett ,  John Clader ,  William J Greenlee ,  Tze-Ming Chan ,  Julie Lee ,  Lili Zhang
Affiliations
  • 1. Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. [email protected]
PMID: 23265902 DOI: 10.1016/j.bmcl.2012.11.054
Abstract

Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor™ led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene γ-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a γ-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering Aβ40-42, compared to their parent compounds.