title: Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 2. Leveraging structure-based drug design to identify analogues with improved pharmacokinetic profiles.
abstract: In the previous report , we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of 1 (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (27, AMG-3969). When administered to db/db mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels.
authors.affiliation: Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, ⊥Department of Pathology, #Department of Pharmaceutics Amgen, Inc. , One Amgen Center Drive, Thousand Oaks, California, 91320 and 360 Binney Street, Cambridge, Massachusetts, 02142, United States.
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
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: Elizabeth
authors.initials: E
authors.lastname: Galbreath
authors.forename: Joan
authors.initials: J
authors.lastname: Helmering
authors.forename: Fang-Tsao
authors.initials: FT
authors.lastname: Hong
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Klaus
authors.initials: K
authors.lastname: Michelsen
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Steve F
authors.initials: SF
authors.lastname: Poon
authors.forename: Darren
authors.initials: D
authors.lastname: Reid
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: Markian M
authors.initials: MM
authors.lastname: Stec
authors.forename: Seifu
authors.initials: S
authors.lastname: Tadesse
authors.forename: Nuria
authors.initials: N
authors.lastname: Tamayo
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Van
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yang
authors.forename: Jiandong
authors.initials: J
authors.lastname: Zhang
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C585748:2-(4-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol; D000480:Alkynes; D001786:Blood Glucose; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D009025:Morpholines; D010879:Piperazines; D013449:Sulfonamides; C080906:glucokinase regulatory protein; D005941:Glucokinase