Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors

  • Bioorg Med Chem Lett. 2013 Feb 1;23(3):844-9. doi: 10.1016/j.bmcl.2012.11.047.
Wen-Lian Wu  1 ,  Theodros Asberom ,  Thomas Bara ,  Chad Bennett ,  Duane A Burnett ,  John Clader ,  Martin Domalski ,  William J Greenlee ,  Hubert Josien ,  Mark McBriar ,  Murali Rajagopalan ,  Monica Vicarel ,  Ruo Xu ,  Lynn A Hyde ,  Robert A Del Vecchio ,  Mary E Cohen-Williams ,  Lixin Song ,  Julie Lee ,  Giuseppe Terracina ,  Qi Zhang ,  Amin Nomeir ,  Eric M Parker ,  Lili Zhang
Affiliations
  • 1. Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA. [email protected]
PMID: 23265892 DOI: 10.1016/j.bmcl.2012.11.047
Abstract

An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's Disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.