Tricyclic sulfones as orally active γ-secretase inhibitors: Synthesis and structure–activity relationship studies

• Published in: Bioorganic & medicinal chemistry letters 2010-06, Vol.20 (12), p.3632-3635
• Main Authors: Sasikumar, T.K., Qiang, Li, Burnett, Duane A., Cole, David, Xu, Ruo, Li, Hongmei, Greenlee, William J., Clader, John, Zhang, Lili, Hyde, Lynn
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - blood; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Biological and medical sciences; Brain Chemistry - drug effects; Medical sciences; Mice; Neuropharmacology; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Sulfone; Sulfones - chemical synthesis; Sulfones - chemistry; Sulfones - pharmacology; γ-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.04.104

Tricyclic sulfones were designed as γ-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.