Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors. Issue 23 (1st December 2016)

• Record Type: Journal Article
• Authors: Wu, Wen-Lian; Burnett, Duane A.; Clader, John; Greenlee, William J.; Jiang, Qin; Hyde, Lynn A.; Del Vecchio, Robert A.; Cohen-Williams, Mary E.; Song, Lixin; Lee, Julie; Terracina, Giuseppe; Zhang, Qi; Nomeir, Amin; Parker, Eric M.; Zhang, Lili
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 23(2016)
• Page Start: 5836
• Page End: 5841
• Publication Date: 2016-12-01
• Subjects: AD Alzheimer's disease -- Aβ β-amyloid -- PS1 presenilin-1 -- PS2 presenilin-2 -- APP amyloid precursor protein -- GSI γ-secretase inhibitor -- SAR structure–activity relationship -- ADME absorption, distribution, metabolism, and excretion -- AUC area under curve -- mCPBA m-chloroperbenzoic acid; Alzheimer's disease -- γ-Secretase inhibitor -- β-Aminosulfone -- Aqueous solubility; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.04.095
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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.