Alpha-hydroxy amides as a novel class of bradykinin B1 selective antagonists.
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Wood
Michael R
MR
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. michael_wood2@merck.com
Schirripa
Kathy M
KM
Kim
June J
JJ
Kuduk
Scott D
SD
Chang
Ronald K
RK
Di Marco
Christina N
CN
DiPardo
Robert M
RM
Wan
Bang-Lin
BL
Murphy
Kathy L
KL
Ransom
Richard W
RW
Chang
Raymond S L
RS
Holahan
Marie A
MA
Cook
Jacquelynn J
JJ
Lemaire
Wei
W
Mosser
Scott D
SD
Bednar
Rodney A
RA
Tang
Cuyue
C
Prueksaritanont
Thomayant
T
Wallace
Audrey A
AA
Mei
Qin
Q
Yu
Jian
J
Bohn
Dennis L
DL
Clayton
Frank C
FC
Adarayn
Emily D
ED
Sitko
Gary R
GR
Leonard
Yvonne M
YM
Freidinger
Roger M
RM
Pettibone
Douglas J
DJ
Bock
Mark G
MG
D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier; D065169:Bradykinin B1 Receptor Antagonists; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D006207:Half-Life; D006801:Humans; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D000577:Amides; D065169:Bradykinin B1 Receptor Antagonists; D065607:Cytochrome P-450 Enzyme Inhibitors