Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors.
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.
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Wen-Lian
WL
Wu
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Duane A
DA
Burnett
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
John
J
Clader
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
William J
WJ
Greenlee
Albany Molecular Research, Inc., 26 Corporate Cir, Albany, NY 12212, USA.
Qin
Q
Jiang
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Lynn A
LA
Hyde
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Robert A
RA
Del Vecchio
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Mary E
ME
Cohen-Williams
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Lixin
L
Song
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Julie
J
Lee
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Giuseppe
G
Terracina
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Qi
Q
Zhang
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Amin
A
Nomeir
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Eric M
EM
Parker
Merck Research Laboratories, 2015 Galloping Hill Rd, Kenilworth, NJ 07033, USA.
Lili
L
Zhang
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001578:Benzopyrans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000882:Haplorhini; D006801:Humans; D051381:Rats; D012995:Solubility; D013450:Sulfones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
D001578:Benzopyrans; D004791:Enzyme Inhibitors; C581851:SCH 900229; D013450:Sulfones; D014867:Water; D053829:Amyloid Precursor Protein Secretases
Alzheimer’s disease; Aqueous solubility; β-Aminosulfone; γ-Secretase inhibitor