title: Aryl sulfonamides containing tetralin allylic amines as potent and selective bradykinin B1 receptor antagonists.
abstract: The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
authors.affiliation: Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, CA 91320, USA. qingyian@amgen.com
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Qian
authors.forename: Aiwen
authors.initials: A
authors.lastname: Li
authors.forename: Kaustav
authors.initials: K
authors.lastname: Biswas
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: Leyla
authors.initials: L
authors.lastname: Arik
authors.forename: Gloria
authors.initials: G
authors.lastname: Biddlecome
authors.forename: Eileen
authors.initials: E
authors.lastname: Johnson
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Gordon Y
authors.initials: GY
authors.lastname: Ng
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Benny C
authors.initials: BC
authors.lastname: Askew
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001596:Benzylamines / Q000737:chemistry*; D065169:Bradykinin B1 Receptor Antagonists; D010146:Pain / Q000188:drug therapy; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D013764:Tetrahydronaphthalenes / Q000737:chemistry*
chemical_list: D001596:Benzylamines; D065169:Bradykinin B1 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C095210:tetralin