title: Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) Binding: Strategic Use of a N → S (nN → σ*S-X) Interaction for Conformational Constraint.
abstract: The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 μM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN → σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Croghan
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Andrews
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Kate S
authors.initials: KS
authors.lastname: Ashton
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Bourbeau
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Joan
authors.initials: J
authors.lastname: Helmering
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Ke
authors.initials: K
authors.lastname: Kong
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Moyer
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Andreas
authors.initials: A
authors.lastname: Reichelt
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Siegmund
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Seifu
authors.initials: S
authors.lastname: Tadesse
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Tegley
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Van
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yang
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Guomin
authors.initials: G
authors.lastname: Yao
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.affiliation: Medicinal Chemistry, ‡Molecular Structure and Characterization, §Pharmacokinetics and Drug Metabolism, ∥Metabolic Disorders Research, and ⊥Pathology, Amgen , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D003593:Cytoplasm / Q000378:metabolism; D005941:Glucokinase / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; C485100:GCKR protein, human; D007004:Hypoglycemic Agents; C000607195:N-((2-amino-5-chloro-3-fluoro-4-pyridinyl)(7-(4-(1-hydroxy-1-methylethyl)-2-pyridinyl)-1-benzothiophen-2-yl)methyl)cyclopropanesulfonamide; D013449:Sulfonamides; D013876:Thiophenes; D005941:Glucokinase