title: Small molecule disruptors of the glucokinase-glucokinase regulatory protein interaction: 3. Structure-activity relationships within the aryl carbinol region of the N-arylsulfonamido-N'-arylpiperazine series.
abstract: We have recently reported a novel approach to increase cytosolic glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, glucokinase regulatory protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK-GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lowered fed blood glucose levels (up to 58%).
authors.affiliation: Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, and ∥Department of Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
authors.forename: Longbin
authors.initials: L
authors.lastname: Liu
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Yang
authors.forename: Kate S
authors.initials: KS
authors.lastname: Ashton
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Samer
authors.initials: S
authors.lastname: Chmait
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Rod
authors.initials: R
authors.lastname: Cupples
authors.forename: Christopher
authors.initials: C
authors.lastname: Fotsch
authors.forename: Joan
authors.initials: J
authors.lastname: Helmering
authors.forename: Steven R
authors.initials: SR
authors.lastname: Jordan
authors.forename: Roxanne K
authors.initials: RK
authors.lastname: Kunz
authors.forename: Lewis D
authors.initials: LD
authors.lastname: Pennington
authors.forename: Steve F
authors.initials: SF
authors.lastname: Poon
authors.forename: Aaron
authors.initials: A
authors.lastname: Siegmund
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: David J
authors.initials: DJ
authors.lastname: Lloyd
authors.forename: Clarence
authors.initials: C
authors.lastname: Hale
authors.forename: David J
authors.initials: DJ
authors.lastname: St Jean
mesh_terms: D000818:Animals; D001682:Biological Availability; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D005941:Glucokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / 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; C000589316:2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol; C000589315:5-((3-(1-propyn-1-yl)-4-(4-(S-(trifluoromethyl)sulfonimidoyl)phenyl)-1-piperazinyl)sulfonyl)-2-pyridinamine; D001786:Blood Glucose; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D010879:Piperazines; D013449:Sulfonamides; C080906:glucokinase regulatory protein; D005941:Glucokinase