title: Discovery of novel, orally active dual NK1/NK2 antagonists.
abstract: Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10(-7)M, in human pulmonary artery pK(B)=8.9 and in human bronchus pK(B)=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, PO Box 15437, Wilmington, DE 19850-5437, USA. peter.bernstein@astrazeneca.com
authors.forename: P R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: D
authors.initials: D
authors.lastname: Aharony
authors.forename: J S
authors.initials: JS
authors.lastname: Albert
authors.forename: D
authors.initials: D
authors.lastname: Andisik
authors.forename: H G
authors.initials: HG
authors.lastname: Barthlow
authors.forename: R
authors.initials: R
authors.lastname: Bialecki
authors.forename: T
authors.initials: T
authors.lastname: Davenport
authors.forename: R F
authors.initials: RF
authors.lastname: Dedinas
authors.forename: B T
authors.initials: BT
authors.lastname: Dembofsky
authors.forename: G
authors.initials: G
authors.lastname: Koether
authors.forename: B J
authors.initials: BJ
authors.lastname: Kosmider
authors.forename: K
authors.initials: K
authors.lastname: Kirkland
authors.forename: C J
authors.initials: CJ
authors.lastname: Ohnmacht
authors.forename: W
authors.initials: W
authors.lastname: Potts
authors.forename: W L
authors.initials: WL
authors.lastname: Rumsey
authors.forename: L
authors.initials: L
authors.lastname: Shen
authors.forename: A
authors.initials: A
authors.lastname: Shenvi
authors.forename: S
authors.initials: S
authors.lastname: Sherwood
authors.forename: D
authors.initials: D
authors.lastname: Stollman
authors.forename: K
authors.initials: K
authors.lastname: Russell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D023421:Models, Animal; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D013454:Sulfoxides; C430919:ZD 6021; C440390:ZD 7944; C073839:SR 48968