A new class of bradykinin 1 receptor antagonists containing the piperidine acetic acid tetralin core.
The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.
Fotsch
Christopher
C
Amgen Inc., Department of Chemistry Research and Development, One Amgen Center Drive, Thousand Oaks, CA 91360, USA. cfotsch@amgen.com
Biddlecome
Gloria
G
Biswas
Kaustav
K
Chen
Jian Jeff
JJ
D'Amico
Derin C
DC
Groneberg
Robert D
RD
Han
Nianhe Bruce
NB
Hsieh
Feng-Yin
FY
Kamassah
Augustus
A
Kumar
Gondi
G
Lester-Zeiner
Dianna
D
Liu
Qingyian
Q
Mareska
David A
DA
Riahi
Babak Bobby
BB
Wang
Yueh-Ju Judy
YJ
Yang
Kevin
K
Zhan
James
J
Zhu
Joe
J
Johnson
Eileen
E
Ng
Gordon
G
Askew
Benny C
BC
D019342:Acetic Acid / Q000737:chemistry; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D065169:Bradykinin B1 Receptor Antagonists; D020128:Inhibitory Concentration 50; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry*
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D065169:Bradykinin B1 Receptor Antagonists; D010880:Piperidines; D013764:Tetrahydronaphthalenes; C032727:piperidine; C095210:tetralin; D019342:Acetic Acid