Discovery of a potent, non-peptide bradykinin B1 receptor antagonist.
Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
Su
Dai-Shi
DS
Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. daishi_su@merck.com
Markowitz
M Kristine
MK
DiPardo
Robert M
RM
Murphy
Kathy L
KL
Harrell
C Meacham
CM
O'Malley
Stacy S
SS
Ransom
Richard W
RW
Chang
Raymond S L
RS
Ha
Sookhee
S
Hess
Fred J
FJ
Pettibone
Douglas J
DJ
Mason
Glenn S
GS
Boyce
Susan
S
Freidinger
Roger M
RM
Bock
Mark G
MG
D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D065168:Bradykinin Receptor Antagonists; D004285:Dogs; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010147:Pain Measurement / Q000187:drug effects; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D000700:Analgesics; D065168:Bradykinin Receptor Antagonists; D011810:Quinoxalines; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin