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.
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. michael_wood2@merck.com
Michael R
MR
Wood
Kathy M
KM
Schirripa
June J
JJ
Kim
Scott D
SD
Kuduk
Ronald K
RK
Chang
Christina N
CN
Di Marco
Robert M
RM
DiPardo
Bang-Lin
BL
Wan
Kathy L
KL
Murphy
Richard W
RW
Ransom
Raymond S L
RS
Chang
Marie A
MA
Holahan
Jacquelynn J
JJ
Cook
Wei
W
Lemaire
Scott D
SD
Mosser
Rodney A
RA
Bednar
Cuyue
C
Tang
Thomayant
T
Prueksaritanont
Audrey A
AA
Wallace
Qin
Q
Mei
Jian
J
Yu
Dennis L
DL
Bohn
Frank C
FC
Clayton
Emily D
ED
Adarayn
Gary R
GR
Sitko
Yvonne M
YM
Leonard
Roger M
RM
Freidinger
Douglas J
DJ
Pettibone
Mark G
MG
Bock
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