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.
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 4, West Point, Pennsylvania 19486, USA. michael_wood2@merck.com
Michael R
MR
Wood
June J
JJ
Kim
Wei
W
Han
Bruce D
BD
Dorsey
Carl F
CF
Homnick
Robert M
RM
DiPardo
Scott D
SD
Kuduk
Tanya
T
MacNeil
Kathy L
KL
Murphy
Edward V
EV
Lis
Richard W
RW
Ransom
Gary L
GL
Stump
Joseph J
JJ
Lynch
Stacey S
SS
O'Malley
Patricia J
PJ
Miller
Tsing-Bau
TB
Chen
Charles M
CM
Harrell
Raymond S L
RS
Chang
Punam
P
Sandhu
Joan D
JD
Ellis
Peter J
PJ
Bondiskey
Douglas J
DJ
Pettibone
Roger M
RM
Freidinger
Mark G
MG
Bock
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