Benzodiazepines as potent and selective bradykinin B1 antagonists.
Antagonism of the bradykinin B(1) receptor was demonstrated to be a potential treatment for chronic pain and inflammation. Novel benzodiazepines were designed that display subnanomolar affinity for the bradykinin B(1) receptor (K(i) = 0.59 nM) and high selectivity against the bradykinin B(2) receptor (K(i) > 10 microM). In vivo efficacy, comparable to morphine, was demonstrated for lead compounds in a rodent hyperalgesia model.
Wood
Michael R
MR
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. michael_wood2@merck.com
Kim
June J
JJ
Han
Wei
W
Dorsey
Bruce D
BD
Homnick
Carl F
CF
DiPardo
Robert M
RM
Kuduk
Scott D
SD
MacNeil
Tanya
T
Murphy
Kathy L
KL
Lis
Edward V
EV
Ransom
Richard W
RW
Stump
Gary L
GL
Lynch
Joseph J
JJ
O'Malley
Stacey S
SS
Miller
Patricia J
PJ
Chen
Tsing-Bau
TB
Harrell
Charles M
CM
Chang
Raymond S L
RS
Sandhu
Punam
P
Ellis
Joan D
JD
Bondiskey
Peter J
PJ
Pettibone
Douglas J
DJ
Freidinger
Roger M
RM
Bock
Mark G
MG
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013329:Structure-Activity Relationship
D065168:Bradykinin Receptor Antagonists; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D001569:Benzodiazepines