Small conformationally restricted piperidine N-arylsulfonamides as orally active gamma-secretase inhibitors.
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Josien
Hubert
H
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07302, USA. hubert.josien@spcorp.com
Bara
Thomas
T
Rajagopalan
Murali
M
Asberom
Theodros
T
Clader
John W
JW
Favreau
Leonard
L
Greenlee
William J
WJ
Hyde
Lynn A
LA
Nomeir
Amin A
AA
Parker
Eric M
EM
Pissarnitski
Dmitri A
DA
Song
Lixin
L
Wong
Gwendolyn T
GT
Zhang
Lili
L
Zhang
Qi
Q
Zhao
Zhiqiang
Z
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D019540:Area Under Curve; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D008970:Molecular Weight; D010088:Oxidoreductases / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D010880:Piperidines; D013449:Sulfonamides; D003577:Cytochrome P-450 Enzyme System; C408695:Cyp3a41a protein, mouse; D010088:Oxidoreductases; D053829:Amyloid Precursor Protein Secretases