Discovery of sulfonamide–pyrazole γ-secretase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 7; pp. 2148 - 2150
• Main Authors: Mattson, Matthew N., Neitzel, Martin L., Quincy, David A., Semko, Christopher M., Garofalo, Albert W., Keim, Pamela S., Konradi, Andrei W., Pleiss, Michael A., Sham, Hing L., Brigham, Elizabeth F., Goldbach, Erich G., Zhang, Hongbin, Sauer, John-Michael, Basi, Guriqbal S.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.04.2010; Elsevier
• Subjects: Alzheimer Disease - drug therapy; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Biological and medical sciences; Crystallography, X-Ray; Humans; Inhibitory Concentration 50; Medical sciences; Models, Molecular; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyrazoles - chemistry; Pyrazoles - pharmacokinetics; Pyrazoles - pharmacology; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Sulfonamide; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; Sulfonamides - pharmacology; γ-secretase inhibitor; Alzheimer’s disease; γ-secretase inhibitor; Sulfonamide; Enzyme; Nitrogen heterocycle; Enzyme inhibitor; Antialzheimer agent; Tricyclic compound; In vitro; Amyloid precursor protein; Peptidases; Metabolic stability; Structure activity relation; Chlorine Organic compounds; Hydrolases; Aspartic endopeptidases; Chemical synthesis; Alzheimer's disease
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.02.050

Utilizing a pharmacophore hypothesis, previously described γ-secretase inhibiting HTS hits were evolved into novel tricyclic sulfonamide–pyrazoles, with high in vitro potency, good brain penetration, low metabolic stability, and high clearance.