Potent nonpeptide antagonists of the bradykinin B1 receptor: structure-activity relationship studies with novel diaminochroman carboxamides.
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
Biswas
Kaustav
K
Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. kbiswas@amgen.com
Li
Aiwen
A
Chen
Jian Jeffrey
JJ
D'Amico
Derin C
DC
Fotsch
Christopher
C
Han
Nianhe
N
Human
Jason
J
Liu
Qingyian
Q
Norman
Mark H
MH
Riahi
Bobby
B
Yuan
Chester
C
Suzuki
Hideo
H
Mareska
David A
DA
Zhan
James
J
Clarke
David E
DE
Toro
Andras
A
Groneberg
Robert D
RD
Burgess
Laurence E
LE
Lester-Zeiner
Dianna
D
Biddlecome
Gloria
G
Manning
Barton H
BH
Arik
Leyla
L
Dong
Hong
H
Huang
Ming
M
Kamassah
Augustus
A
Loeloff
Richard
R
Sun
Hong
H
Hsieh
Feng-Yin
FY
Kumar
Gondi
G
Ng
Gordon Y
GY
Hungate
Randall W
RW
Askew
Benny C
BC
Johnson
Eileen
E
D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D065169:Bradykinin B1 Receptor Antagonists; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
C520646:3-(4-fluorophenyl)-N-(7-(piperidin-1-ylmethyl)chroman-4-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)propanamide; D000577:Amides; D000700:Analgesics; D001578:Benzopyrans; D065169:Bradykinin B1 Receptor Antagonists; D002839:Chromans; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D002118:Calcium