title: Discovery of potent, orally bioavailable phthalazinone bradykinin B1 receptor antagonists.
abstract: The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.
authors: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States. kbiswas@amgen.com
authors: Kaustav
authors: K
authors: Biswas
authors: Tanya A N
authors: TA
authors: Peterkin
authors: Marian C
authors: MC
authors: Bryan
authors: Leyla
authors: L
authors: Arik
authors: Sonya G
authors: SG
authors: Lehto
authors: Hong
authors: H
authors: Sun
authors: Feng-Yin
authors: FY
authors: Hsieh
authors: Cen
authors: C
authors: Xu
authors: Robert T
authors: RT
authors: Fremeau
authors: Jennifer R
authors: JR
authors: Allen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D065169:Bradykinin B1 Receptor Antagonists; D004285:Dogs; D006801:Humans; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D010793:Phthalazines