title: Potent nonpeptide antagonists of the bradykinin B1 receptor: structure-activity relationship studies with novel diaminochroman carboxamides.
abstract: The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, USA. kbiswas@amgen.com
authors.forename: Kaustav
authors.initials: K
authors.lastname: Biswas
authors.forename: Aiwen
authors.initials: A
authors.lastname: Li
authors.forename: Jian Jeffrey
authors.initials: JJ
authors.lastname: Chen
authors.forename: Derin C
authors.initials: DC
authors.lastname: D'Amico
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Nianhe
authors.initials: N
authors.lastname: Han
authors.forename: Jason
authors.initials: J
authors.lastname: Human
authors.forename: Qingyian
authors.initials: Q
authors.lastname: Liu
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Bobby
authors.initials: B
authors.lastname: Riahi
authors.forename: Chester
authors.initials: C
authors.lastname: Yuan
authors.forename: Hideo
authors.initials: H
authors.lastname: Suzuki
authors.forename: David A
authors.initials: DA
authors.lastname: Mareska
authors.forename: James
authors.initials: J
authors.lastname: Zhan
authors.forename: David E
authors.initials: DE
authors.lastname: Clarke
authors.forename: Andras
authors.initials: A
authors.lastname: Toro
authors.forename: Robert D
authors.initials: RD
authors.lastname: Groneberg
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Burgess
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Gloria
authors.initials: G
authors.lastname: Biddlecome
authors.forename: Barton H
authors.initials: BH
authors.lastname: Manning
authors.forename: Leyla
authors.initials: L
authors.lastname: Arik
authors.forename: Hong
authors.initials: H
authors.lastname: Dong
authors.forename: Ming
authors.initials: M
authors.lastname: Huang
authors.forename: Augustus
authors.initials: A
authors.lastname: Kamassah
authors.forename: Richard
authors.initials: R
authors.lastname: Loeloff
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Feng-Yin
authors.initials: FY
authors.lastname: Hsieh
authors.forename: Gondi
authors.initials: G
authors.lastname: Kumar
authors.forename: Gordon Y
authors.initials: GY
authors.lastname: Ng
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Benny C
authors.initials: BC
authors.lastname: Askew
authors.forename: Eileen
authors.initials: E
authors.lastname: Johnson
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D065169:Bradykinin B1 Receptor Antagonists; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002839:Chromans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008861:Microsomes / Q000378:metabolism; D010146:Pain / Q000188:drug therapy; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1 / Q000819:agonists; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C520646:3-(4-fluorophenyl)-N-(7-(piperidin-1-ylmethyl)chroman-4-yl)-3-(3-(trifluoromethyl)phenylsulfonamido)propanamide; D000577:Amides; D000700:Analgesics; D001578:Benzopyrans; D065169:Bradykinin B1 Receptor Antagonists; D002839:Chromans; D043783:Receptor, Bradykinin B1; D013449:Sulfonamides; D002118:Calcium