Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
The glucokinase-glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Nuria A
NA
Tamayo
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Mark H
MH
Norman
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Michael D
MD
Bartberger
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Fang-Tsao
FT
Hong
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Yunxin
Y
Bo
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Longbin
L
Liu
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Nobuko
N
Nishimura
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Kevin C
KC
Yang
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Seifu
S
Tadesse
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Christopher
C
Fotsch
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Jie
J
Chen
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Samer
S
Chmait
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Rod
R
Cupples
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Clarence
C
Hale
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Steven R
SR
Jordan
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
David J
DJ
Lloyd
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Glenn
G
Sivits
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Gwyneth
G
Van
†Department of Therapeutic Discovery-Medicinal Chemistry, ‡Department of Therapeutic Discovery-Molecular Structure and Characterization, §Department of Metabolic Disorders, ∥Department of Pharmacokinetics and Drug Metabolism, and ⊥Department of Pathology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
David J
DJ
St Jean
D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D005941:Glucokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology
C000601370:2-(4-(5-((6-aminopyridin-3-yl)sulfonyl)thiazol-2-yl)-3-chlorophenyl)propane-1,2-diol; D000631:Aminopyridines; D002352:Carrier Proteins; D007004:Hypoglycemic Agents; D054852:Small Molecule Libraries; D013450:Sulfones; C080906:glucokinase regulatory protein; D005941:Glucokinase; D005947:Glucose