title: Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 4. Exploration of a novel binding pocket.
abstract: Structure-activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N'-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the glucokinase-glucokinase regulatory protein (GK-GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 ("shelf region") as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50=0.005 μM and EC50=0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose.
authors.affiliation: Departments of Therapeutic Discovery-Medicinal Chemistry, ‡ Therapeutic Discovery-Molecular Structure, §Pharmacokinetics and Drug Metabolism, and ∥Metabolic Disorders, Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Kate S
authors.initials: KS
authors.lastname: Ashton
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: Seifu
authors.initials: S
authors.lastname: Tadesse
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D005941:Glucokinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002352:Carrier Proteins; D010879:Piperazines; D011725:Pyridines; D054852:Small Molecule Libraries; C080906:glucokinase regulatory protein; D005941:Glucokinase; C023666:pyridine