title: Dual neurokinin NK(1)/NK(2) 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.
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.
authors.affiliation: Pharma Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. marc.gerspacher@pharma.novartis.com
authors.forename: M
authors.initials: M
authors.lastname: Gerspacher
authors.forename: L
authors.initials: L
authors.lastname: La Vecchia
authors.forename: R
authors.initials: R
authors.lastname: Mah
authors.forename: A
authors.initials: A
authors.lastname: von Sprecher
authors.forename: G P
authors.initials: GP
authors.lastname: Anderson
authors.forename: N
authors.initials: N
authors.lastname: Subramanian
authors.forename: K
authors.initials: K
authors.lastname: Hauser
authors.forename: H
authors.initials: H
authors.lastname: Bammerlin
authors.forename: S
authors.initials: S
authors.lastname: Kimmel
authors.forename: V
authors.initials: V
authors.lastname: Pawelzik
authors.forename: K
authors.initials: K
authors.lastname: Ryffel
authors.forename: H A
authors.initials: HA
authors.lastname: Ball
mesh_terms: D000818:Animals; D001372:Aza Compounds / Q000737:chemistry* / Q000494:pharmacology*; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C448384:3-(N'-3,5-bis(trifluoromethyl)benzoyl-N-(3,4-dichlorobenzyl)-N'-methylhydrazino)-N-(-2-oxo-azepan-3-yl)propionamide; D001372:Aza Compounds; D001549:Benzamides; C448383:DNK 333; D006834:Hydrazines; C415227:N-(1-(4-chloro-benzyl)-3-(2-oxo-azepan-3-ylcarbamoyl)-allyl)-N-methyl-3,5,-bis-trifluoromethyl-benzamide; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2