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.

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