ABSTRACT
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.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Cyclooctanes/pharmacology , Protease Inhibitors/pharmacology , Thiadiazoles/pharmacology , Administration, Oral , Animals , Cyclooctanes/administration & dosage , Cyclooctanes/chemical synthesis , Cyclooctanes/pharmacokinetics , Inhibitory Concentration 50 , Mice , Protease Inhibitors/administration & dosage , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Thiadiazoles/administration & dosage , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacokineticsABSTRACT
A series of 4,4-disubstituted cyclohexylamine NK(1) antagonists containing a lactam ring is described. The compounds are brain penetrant and activity is demonstrated in a ferret emesis model.
Subject(s)
Antiemetics/chemical synthesis , Antiemetics/pharmacology , Lactams/chemistry , Lactams/pharmacology , Tachykinins/antagonists & inhibitors , Amides/chemistry , Animals , Antiemetics/chemistry , Gerbillinae , Humans , Inhibitory Concentration 50 , Lactams/chemical synthesis , Methylation , Molecular Structure , Receptors, Neurokinin-1/metabolism , Structure-Activity Relationship , Tachykinins/metabolismABSTRACT
A series of novel 4,4-disubstituted cyclohexylamine based NK(1) antagonists is described. The effect of changes to the C(1)-C(4) relative stereochemistry on the cyclohexane ring and replacements for the flexible linker are discussed, leading to the identification of compounds with high affinity and good in vivo duration of action.
Subject(s)
Cyclohexylamines/chemical synthesis , Cyclohexylamines/pharmacology , Neurokinin-1 Receptor Antagonists , Animals , Binding Sites , CHO Cells , Central Nervous System/drug effects , Central Nervous System/metabolism , Cricetinae , Cyclohexylamines/pharmacokinetics , Gerbillinae , Inhibitory Concentration 50 , Molecular Conformation , Radioligand Assay , Receptors, Neurokinin-1/chemistry , Structure-Activity RelationshipABSTRACT
A series of novel 4,4-disubstituted cyclohexylamines as NK(1) receptor antagonists is described: modifications to the amine moiety retain NK(1) receptor binding affinity whilst disrupting I(Kr) affinity.
