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

Nobuko Nishimura; Mark H Norman; Longbin Liu; Kevin C Yang; Kate S Ashton; Michael D Bartberger; Samer Chmait; Jie Chen; Rod Cupples; Christopher Fotsch; Joan Helmering; Steven R Jordan; Roxanne K Kunz; Lewis D Pennington; Steve F Poon; Aaron Siegmund; Glenn Sivits; David J Lloyd; Clarence Hale; David J St Jean Jr

doi:10.1021/jm5000497

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

J Med Chem. 2014 Apr 10;57(7):3094-116. doi: 10.1021/jm5000497. Epub 2014 Mar 31.

Affiliation

¹ 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.

PMID: 24611879
DOI: 10.1021/jm5000497

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%).

MeSH terms

Animals
Biological Availability
Blood Glucose / metabolism
Carrier Proteins / antagonists & inhibitors*
Carrier Proteins / metabolism
Crystallography, X-Ray
Diabetes Mellitus / drug therapy*
Diabetes Mellitus / metabolism
Disease Models, Animal
Glucokinase / antagonists & inhibitors*
Glucokinase / metabolism
Hepatocytes / drug effects*
Hepatocytes / metabolism
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Mice
Microsomes, Liver / drug effects*
Microsomes, Liver / metabolism
Models, Molecular
Piperazines / chemistry*
Piperazines / pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship
Sulfonamides / chemistry
Sulfonamides / pharmacology*

Substances

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
2-(6-(4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)-3-pyridinyl)-1,1,1-trifluoro-2-propanol
5-((3-(1-propyn-1-yl)-4-(4-(S-(trifluoromethyl)sulfonimidoyl)phenyl)-1-piperazinyl)sulfonyl)-2-pyridinamine
Blood Glucose
Carrier Proteins
Hypoglycemic Agents
Piperazines
Sulfonamides
glucokinase regulatory protein
Glucokinase

Associated data

PDB/4OHK
PDB/4OHM
PDB/4OHO
PDB/4OHP