Discovery of amide and heteroaryl isosteres as carbamate replacements in a series of orally active gamma-secretase inhibitors.
The design of amide and heteroaryl amide isosteres as replacements for the carbamate substructure in previously disclosed 2,6-disubstituted piperidine N-arylsulfonamides is described. In several cases, amides lessened CYP liabilities in this class of gamma-secretase inhibitors. Selected compounds showed significant reduction of Abeta levels upon oral dosing in a transgenic murine model of Alzheimer's disease.
McBriar
Mark D
MD
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. mark.mcbriar@spcorp.com
Clader
John W
JW
Chu
Inhou
I
Del Vecchio
Robert A
RA
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
Zhang
Lili
L
Zhao
Zhiqiang
Z
D000577:Amides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D002219:Carbamates / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D010069:Oxadiazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D016229:Amyloid beta-Peptides; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D006571:Heterocyclic Compounds; D010069:Oxadiazoles; D010880:Piperidines; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases