Journal article

Dual neurokinin NK1/NK2 antagonists: N-[(R,R)-(E)-1-arylmethyl-3-(2-oxo-azepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamides and 3-[N '-3,5-bis(trifluoromethyl)benzoyl-N-arylmethyl-N '-methylhydrazino]-N-[(R)-2-oxo-azepan-3-yl] propionamides

M Gerspacher, L La Vecchia, R Mah, A von Sprecher, GP Anderson, N Subramanian, K Hauser, H Bammerlin, S Kimmel, V Pawelzik, K Ryffel, HA Ball

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2001

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.

University of Melbourne Researchers