Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)
| Autor: | John D. Knafels, David Price, Matthew Gorgoglione, Aaron C. Smith, Kevin D. Parris, Jemy A. Gutierrez, Magee Thomas Victor, Erik Alphie Lachapelle, Yan Weng, Edward L. Conn, Jeffrey A. Pfefferkorn, Jane M. Withka, Kim Huard, Matthew S. Dowling, Timothy A. Subashi, Trenton T. Ross, Benjamin A. Thuma, Kris A. Borzilleri, Paul A. Amor, Jeffrey S. Culp, Meihua Tu, Sylvie Perez, Jayvardhan Pandit, Andre Shavnya, Boris A. Chrunyk, Gang Xing, John D. Weaver, Yang Cong, Kay Ahn, David A. Beebe, Brian Raymer, Gregory J. Tesz, Steven B. Coffey |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Pyridines Pharmacology Crystallography X-Ray 01 natural sciences Fructokinases Rats Sprague-Dawley Small Molecule Libraries 03 medical and health sciences Insulin resistance In vivo Drug Discovery medicine Animals Humans Transferase Protein Kinase Inhibitors chemistry.chemical_classification 010405 organic chemistry Chemistry Metabolism medicine.disease Small molecule Rats 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology Fructose metabolism Enzyme Biochemistry Drug Design Molecular Medicine Steatosis |
| Zdroj: | Journal of Medicinal Chemistry. 60:7835-7849 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.7b00947 |
| Popis: | Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin resistance in humans. Since ketohexokinase (KHK) is the principal enzyme responsible for fructose metabolism, identification of a selective KHK inhibitor may help to further elucidate the effect of KHK inhibition on these metabolic disorders. Until now, studies on KHK inhibition with small molecules have been limited due to the lack of viable in vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties suitable for evaluating KHK inhibition in rat models. Key structural features interacting with KHK were discovered through fragment-based screening and subsequent optimization using structure-based drug design, and parallel medicinal chemistry led to the identification of pyridine 12. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|