title: 3-Oxo-2-piperazinyl acetamides as potent bradykinin B1 receptor antagonists for the treatment of pain and inflammation.
abstract: The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States. jianc@amgen.com
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Nguyen
authors.forename: Derin C
authors.initials: DC
authors.lastname: D'Amico
authors.forename: Wenyuan
authors.initials: W
authors.lastname: Qian
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Aya
authors.forename: Kaustav
authors.initials: K
authors.lastname: Biswas
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Tanya A N
authors.initials: TA
authors.lastname: Peterkin
authors.forename: Kevin
authors.initials: K
authors.lastname: Yang
authors.forename: Jiawang
authors.initials: J
authors.lastname: Zhu
authors.forename: Babak Bobby
authors.initials: BB
authors.lastname: Riahi
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Neil G
authors.initials: NG
authors.lastname: Andersen
authors.forename: John T
authors.initials: JT
authors.lastname: Colyer
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Faul
authors.forename: Augustus
authors.initials: A
authors.lastname: Kamassah
authors.forename: Judy
authors.initials: J
authors.lastname: Wang
authors.forename: Janan
authors.initials: J
authors.lastname: Jona
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Eileen
authors.initials: E
authors.lastname: Johnson
authors.forename: Benny C
authors.initials: BC
authors.lastname: Askew
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D004285:Dogs; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D051379:Mice; D023421:Models, Animal; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D011817:Rabbits; D051381:Rats; D043783:Receptor, Bradykinin B1 / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D065169:Bradykinin B1 Receptor Antagonists; D010879:Piperazines; D043783:Receptor, Bradykinin B1