Discovery of sulfonamide–pyrazole γ-secretase inhibitors

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.

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2148-2150
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Beschreibung
Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.02.050