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.
Josien
Hubert
H
Department of CV and CNS Medicinal Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. hubert.josien@spcorp.com
Bara
Thomas
T
Rajagopalan
Murali
M
Clader
John W
JW
Greenlee
William J
WJ
Favreau
Leonard
L
Hyde
Lynn A
LA
Nomeir
Amin A
AA
Parker
Eric M
EM
Song
Lixin
L
Zhang
Lili
L
Zhang
Qi
Q
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