Novel orally active morpholine N-arylsulfonamides gamma-secretase inhibitors with low CYP 3A4 liability.
A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-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 Abeta levels in Tg CRND8 mice upon oral administration were identified.
Department of CV and CNS Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. hubert.josien@spcorp.com
Hubert
H
Josien
Thomas
T
Bara
Murali
M
Rajagopalan
John W
JW
Clader
William J
WJ
Greenlee
Leonard
L
Favreau
Lynn A
LA
Hyde
Amin A
AA
Nomeir
Eric M
EM
Parker
Lixin
L
Song
Lili
L
Zhang
Qi
Q
Zhang
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D009025:Morpholines; D013449:Sulfonamides; C037574:morpholine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D053829:Amyloid Precursor Protein Secretases