Cyclic sulfamide gamma-secretase inhibitors.
A novel series of N-alkyl-substituted cyclic sulfamides were developed from a screening hit. Chemistries were developed which allowed surveys of N-alkyl groups and amines resulting in the identification of N-trifluoroethyl-substituted cyclic sulfamides with good in vitro and in vivo gamma-secretase activity. One compound with subnanomolar activity elicited a reduction in brain Abeta40 after oral dosing in APP-YAC mice.
Sparey
Tim
T
Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. tim_sparey@merck.com
Beher
Dirk
D
Best
Jonathan
J
Biba
Mirlinda
M
Castro
José L
JL
Clarke
Earl
E
Hannam
Joanne
J
Harrison
Timothy
T
Lewis
Huw
H
Madin
Andrew
A
Shearman
Mark
M
Sohal
Bindi
B
Tsou
Nancy
N
Welch
Christopher
C
Wrigley
Jonathan
J
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001923:Brain Chemistry; D010450:Endopeptidases; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D051379:Mice; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013451:Sulfonic Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D006571:Heterocyclic Compounds; D011480:Protease Inhibitors; D013451:Sulfonic Acids; C005741:sulfamic acid; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse