title: Discovery of a potent, non-peptide bradykinin B1 receptor antagonist.
abstract: Bradykinin (BK) plays an important role in the pathophysiological processes accompanying pain and inflammation. Selective bradykinin B1 receptor antagonists have been shown to be anti-nociceptive in animal models and could be novel therapeutic agents for the treatment of pain and inflammation. We have explored chemical modifications in a series of dihydroquinoxalinone sulfonamides to evaluate the effects of various structural changes on biological activity. The optimization of a screening lead compound, facilitated by a homology model of the BK B1 receptor, culminated in the discovery of a potent human BK B1 receptor antagonist. Results from site-directed mutagenesis studies and experiments in an animal pain model are presented.
authors.affiliation: Departments of Medicinal Chemistry and Neuroscience, Merck Research Laboratories, West Point, PA 19486, USA. daishi_su@merck.com
authors.forename: Dai-Shi
authors.initials: DS
authors.lastname: Su
authors.forename: M Kristine
authors.initials: MK
authors.lastname: Markowitz
authors.forename: Robert M
authors.initials: RM
authors.lastname: DiPardo
authors.forename: Kathy L
authors.initials: KL
authors.lastname: Murphy
authors.forename: C Meacham
authors.initials: CM
authors.lastname: Harrell
authors.forename: Stacy S
authors.initials: SS
authors.lastname: O'Malley
authors.forename: Richard W
authors.initials: RW
authors.lastname: Ransom
authors.forename: Raymond S L
authors.initials: RS
authors.lastname: Chang
authors.forename: Sookhee
authors.initials: S
authors.lastname: Ha
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Hess
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Pettibone
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Mason
authors.forename: Susan
authors.initials: S
authors.lastname: Boyce
authors.forename: Roger M
authors.initials: RM
authors.lastname: Freidinger
authors.forename: Mark G
authors.initials: MG
authors.lastname: Bock
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D065168:Bradykinin Receptor Antagonists; D004285:Dogs; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D010147:Pain Measurement / Q000187:drug effects; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D065168:Bradykinin Receptor Antagonists; D011810:Quinoxalines; D043783:Receptor, Bradykinin B1; D018002:Receptors, Bradykinin