Potent and orally bioavailable non-peptide antagonists at the human bradykinin B(1) receptor based on a 2-alkylamino-5-sulfamoylbenzamide core.
The bradykinin B(1) receptor is rapidly induced after inflammation or tissue trauma and appears to play an important role in the maintenance of hyperalgesia in inflammatory conditions. Here, we describe the optimization process to identify novel, potent non-peptide human B(1) receptor antagonists based on a 2-alkylamino-5-sulfamoylbenzamide core. Optimized derivatives are selective, functional B(1) antagonists with low nanomolar affinity and exhibit oral bioavailability in animals.
Ritchie
Timothy J
TJ
Dziadulewicz
Edward K
EK
Culshaw
Andrew J
AJ
Müller
Werner
W
Burgess
Gillian M
GM
Bloomfield
Graham C
GC
Drake
Gillian S
GS
Dunstan
Andrew R
AR
Beattie
David
D
Hughes
Glyn A
GA
Ganju
Pam
P
McIntyre
Peter
P
Bevan
Stuart J
SJ
Davis
Clare
C
Yaqoob
Mohammed
M
D000284:Administration, Oral; D000588:Amines / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry; D001682:Biological Availability; D065169:Bradykinin B1 Receptor Antagonists; D002264:Carboxylic Acids / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology
D000588:Amines; D000596:Amino Acids; D065169:Bradykinin B1 Receptor Antagonists; D002264:Carboxylic Acids; D010455:Peptides; D062367:ortho-Aminobenzoates; C000219:anthranilamide