Novel orally bioavailable gamma-secretase inhibitors with excellent in vivo activity.
The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED(50) of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.
Keown
Linda E
LE
Department of Medicinal Chemistry, Molecular and Cellular Neuroscience, and in Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp & Dohme Research Laboratories, Terlings Park, Harlow, Essex, UK. keown.linda@yahoo.co.uk
Collins
Ian
I
Cooper
Laura C
LC
Harrison
Timothy
T
Madin
Andrew
A
Mistry
Jayesh
J
Reilly
Michael
M
Shaimi
Mohamed
M
Welch
Christopher J
CJ
Clarke
Earl E
EE
Lewis
Huw D
HD
Wrigley
Jonathan D J
JD
Best
Jonathan D
JD
Murray
Fraser
F
Shearman
Mark S
MS
D000284:Administration, Oral; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D000818:Animals; D034242:Cyclooctanes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D013830:Thiadiazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*
C541698:2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methylpyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro(6,9-methanobenzocycloocten-11,3'-(1,2,5)thiadiazole) 1',1'-dioxide; D016229:Amyloid beta-Peptides; D034242:Cyclooctanes; D011480:Protease Inhibitors; D013830:Thiadiazoles; D053829:Amyloid Precursor Protein Secretases