title: Discovery of a potent and novel motilin agonist.
abstract: A novel series of dihydro- and tetrahydrotriazolopyridazine-1,3-dione-based amino acid derivatives were identified as very potent motilin receptor agonists. Incorporating one additional phenylethyl glycinamide subunit to 1 (EC(50) = 660 nM) was found to improve in vitro potency approximately 3000-fold, resulting in compound 10 (EC(50) = 0.22 nM). The more potent enantiomer 11A has an EC(50) of 0.047 nM in the motilin receptor functional assay and a K(i) of 0.7 nM in the binding assay. In addition, compound 11A was shown to have a significantly reduced tendency to cause receptor desensitization as compared with the motilin receptor agonist ABT-229.
authors.affiliation: Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08643-5400, USA. james.li@bms.com
authors.forename: James J
authors.initials: JJ
authors.lastname: Li
authors.forename: Hann-Guang
authors.initials: HG
authors.lastname: Chao
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Tino
authors.forename: R Michael
authors.initials: RM
authors.lastname: Lawrence
authors.forename: William R
authors.initials: WR
authors.lastname: Ewing
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Ma
authors.forename: Mujing
authors.initials: M
authors.lastname: Yan
authors.forename: Dorothy
authors.initials: D
authors.lastname: Slusarchyk
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Seethala
authors.forename: Huabin
authors.initials: H
authors.lastname: Sun
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.forename: Neil T
authors.initials: NT
authors.lastname: Burford
authors.forename: Robert H
authors.initials: RH
authors.lastname: Stoffel
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Salyan
authors.forename: Cindy Y
authors.initials: CY
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Witkus
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.forename: Adam
authors.initials: A
authors.lastname: Rich
authors.forename: David A
authors.initials: DA
authors.lastname: Gordon
mesh_terms: D020013:Calcium Signaling / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009037:Motilin / Q000819:agonists*; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists* / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D011724:Pyridazines; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D014230:Triazoles; C050802:motilin receptor; D009037:Motilin