Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors

  • Bioorg Med Chem Lett. 2016 Dec 1;26(23):5836-5841. doi: 10.1016/j.bmcl.2016.04.095.
Wen-Lian Wu  1 ,  Duane A Burnett  1 ,  John Clader  1 ,  William J Greenlee  1 ,  Qin Jiang  2 ,  Lynn A Hyde  1 ,  Robert A Del Vecchio  1 ,  Mary E Cohen-Williams  1 ,  Lixin Song  1 ,  Julie Lee  1 ,  Giuseppe Terracina  1 ,  Qi Zhang  1 ,  Amin Nomeir  1 ,  Eric M Parker  1 ,  Lili Zhang  1
Affiliations
  • 1. Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
  • 2. Albany Molecular Research, Inc., 26 Corporate Cir, Albany, NY 12212, USA.
PMID: 27836402 DOI: 10.1016/j.bmcl.2016.04.095
Abstract

In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective γ-secretase inhibitor for the treatment of Alzheimer's Disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble β-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy.

Keywords
Alzheimer’s disease; Aqueous solubility; β-Aminosulfone; γ-Secretase inhibitor.