Preparation and optimization of a series of 3-carboxamido-5-phenacylaminopyrazole bradykinin B1 receptor antagonists.
The B1 receptor is an attractive target for the treatment of pain and inflammation. A series of 3-carboxamido-5-phenacylamino pyrazole B1 receptor antagonists are described that exhibit good potency against B1 and high selectivity over B2. Initially, N-unsubstituted pyrazoles were studied, but these compounds suffered from extensive glucuronidation in primates. This difficulty could be surmounted by the use of N-substituted pyrazoles. Optimization efforts culminated in compound 41, which has high receptor potency and metabolic stability.
Dressen
Darren
D
Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, California 94080, USA. al.garofalo@elan.com
Garofalo
Albert W
AW
Hawkinson
Jon
J
Hom
Dennis
D
Jagodzinski
Jacek
J
Marugg
Jennifer L
JL
Neitzel
Martin L
ML
Pleiss
Michael A
MA
Szoke
Balazs
B
Tung
Jay S
JS
Wone
David W G
DW
Wu
Jing
J
Zhang
Heather
H
D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D065169:Bradykinin B1 Receptor Antagonists; D018360:Crystallography, X-Ray; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000166:cytology; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D013329:Structure-Activity Relationship
C524273:4-bromo-5-((2-chlorobenzoyl)amino)-1-phenyl-N-(2-(1-(4-pyridinyl)-4-piperidinyl)ethyl)-1H-pyrazole-3-carboxamide; D001549:Benzamides; D065169:Bradykinin B1 Receptor Antagonists; D011720:Pyrazoles