Novel orally active morpholine N-arylsulfonamides γ-secretase inhibitors with low CYP 3A4 liability

• Published in: Bioorganic & medicinal chemistry letters 2009-11, Vol.19 (21), p.6032-6037
• Main Authors: Josien, Hubert, Bara, Thomas, Rajagopalan, Murali, Clader, John W., Greenlee, William J., Favreau, Leonard, Hyde, Lynn A., Nomeir, Amin A., Parker, Eric M., Song, Lixin, Zhang, Lili, Zhang, Qi
• Format: Article
• Language: English
• Subjects: Administration, Oral; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; CYP 3A4; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors; Disease Models, Animal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Humans; Inhibitor; Mice; Mice, Transgenic; Morpholine; Morpholines - chemical synthesis; Morpholines - chemistry; Morpholines - pharmacokinetics; Rats; Sulfonamide; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacokinetics; γ-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.09.055

The design of a new class of N-arylsulfonamide γ-secretase inhibitors based on the introduction of a morpholine core is reported. Compounds devoid of CYP 3A liability and active orally in a Tg CRND8 mice model of Alzheimer’s disease were obtained. A new class of 2,6-disubstituted morpholine N-arylsulfonamide γ-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Aβ levels in Tg CRND8 mice upon oral administration were identified.