Abstract
Based on the structure of N-[(R,R)-(E)-1-(4-chlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1), attempts to improve the NK(2) affinity have resulted in the discovery of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (9, DNK333) exhibiting a 5-fold improved affinity to the NK(2) receptor in comparison to 1. Simplification of the structure via elimination of a chiral centre led to 3-[N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl]propionamide (22), a potent and fairly balanced NK(1)/NK(2) antagonist.
MeSH terms
-
Animals
-
Aza Compounds / chemistry*
-
Aza Compounds / pharmacology*
-
Benzamides / chemistry*
-
Benzamides / pharmacology*
-
CHO Cells
-
Cricetinae
-
Drug Evaluation, Preclinical
-
Humans
-
Hydrazines / pharmacology*
-
Inhibitory Concentration 50
-
Neurokinin-1 Receptor Antagonists*
-
Receptors, Neurokinin-1 / metabolism
-
Receptors, Neurokinin-2 / antagonists & inhibitors*
-
Receptors, Neurokinin-2 / metabolism
-
Structure-Activity Relationship
Substances
-
3-(N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino)-N-(-2-oxo-azepan-3-yl)propionamide
-
Aza Compounds
-
Benzamides
-
DNK 333
-
Hydrazines
-
N-(1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl)-N-methyl-3,5,-bis-trifluoromethyl-benzamide
-
Neurokinin-1 Receptor Antagonists
-
Receptors, Neurokinin-1
-
Receptors, Neurokinin-2