title: Stereoselective preparation of N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3- (2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide, a potent and orally active dual neurokinin NK(1)/NK(2) receptor antagonist.
abstract: In a program aimed at the development of neurokinin antagonists, N-[(R,R)-(E)-1-(3,4-dichlorobenzyl)-3-(2-oxoazepan-3-yl)carbamoyl]allyl-N-methyl-3,5-bis(trifluoromethyl)benzamide (1, DNK333) has been discovered as a potent and balanced neurokinin (tachykinin) NK(1)/NK(2) receptor antagonist. Enantiomerically pure (>99.5% ee) 1 can be prepared in 6 + 1 synthetic steps starting from commercially available optically active BOC-d-3,4-dichlorophenylalanine in an overall yield of ca. 25-30%. 1 showed potent affinities to cloned human NK(1) (pK(i) = 8.38) and NK(2) (pK(i) = 8.02) receptors. When 1 was compared to the other possible three diastereoisomers, it could be demonstrated that only the R,R-isomer (1) exhibits potent and balanced affinity for the cloned human NK(1) and NK(2) receptors. 1 exhibited favorable pharmacokinetic properties in guinea pigs following oral administration and demonstrated in vivo activity in pharmacological models of substance P- and neurokinin A (NKA)-induced bronchoconstriction in guinea pigs after intravenous and in squirrel monkeys after oral application.
authors.affiliation: Pharma Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. marc.gerspacher@pharma.novartis.com
authors.forename: Marc
authors.initials: M
authors.lastname: Gerspacher
authors.forename: Christine
authors.initials: C
authors.lastname: Lewis
authors.forename: Howard A
authors.initials: HA
authors.lastname: Ball
authors.forename: Colin
authors.initials: C
authors.lastname: Howes
authors.forename: Natarajan
authors.initials: N
authors.lastname: Subramanian
authors.forename: Karin
authors.initials: K
authors.lastname: Ryffel
authors.forename: John R
authors.initials: JR
authors.lastname: Fozard
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016084:Bronchoconstriction / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012453:Saimiri; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D001549:Benzamides; C448383:DNK 333; D064729:Neurokinin-1 Receptor Antagonists; D018041:Receptors, Neurokinin-2