title: Preparation and optimization of a series of 3-carboxamido-5-phenacylaminopyrazole bradykinin B1 receptor antagonists.
abstract: 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.
authors: Elan Pharmaceuticals, Inc., 800 Gateway Boulevard, South San Francisco, California 94080, USA. al.garofalo@elan.com
authors: Darren
authors: D
authors: Dressen
authors: Albert W
authors: AW
authors: Garofalo
authors: Jon
authors: J
authors: Hawkinson
authors: Dennis
authors: D
authors: Hom
authors: Jacek
authors: J
authors: Jagodzinski
authors: Jennifer L
authors: JL
authors: Marugg
authors: Martin L
authors: ML
authors: Neitzel
authors: Michael A
authors: MA
authors: Pleiss
authors: Balazs
authors: B
authors: Szoke
authors: Jay S
authors: JS
authors: Tung
authors: David W G
authors: DW
authors: Wone
authors: Jing
authors: J
authors: Wu
authors: Heather
authors: H
authors: Zhang
mesh_terms: 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
chemical_list: 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