Aryl sulfonamides containing tetralin allylic amines as potent and selective bradykinin B1 receptor antagonists.
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.
Liu
Qingyian
Q
Chemistry Research and Discovery, Amgen Inc., Thousand Oaks, CA 91320, USA. qingyian@amgen.com
Qian
Wenyuan
W
Li
Aiwen
A
Biswas
Kaustav
K
Chen
Jian Jeffrey
JJ
Fotsch
Christopher
C
Han
Nianhe
N
Yuan
Chester
C
Arik
Leyla
L
Biddlecome
Gloria
G
Johnson
Eileen
E
Kumar
Gondi
G
Lester-Zeiner
Dianna
D
Ng
Gordon Y
GY
Hungate
Randall W
RW
Askew
Benny C
BC
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*
D001596:Benzylamines; D065169:Bradykinin B1 Receptor Antagonists; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; C095210:tetralin