Structure-based de novo design and synthesis of aminothiazole-based p38 MAP kinase inhibitors.

Abstract

p38 mitogen-activated protein kinase (MAPK) is a promising target for the development of therapeutics for various immunological diseases. We designed and synthesized aminothiazole-based p38 MAPK inhibitors of with IC50 values ranging from 0.1 to 2 μM by means of the structure-based de novo design of phenyl-(2-phenylamino-thiazol-5-yl)-methanone scaffold. Because these newly identified inhibitors were also screened for having desirable physicochemical properties as a drug candidate, they deserve consideration for further investigation as anti-inflammatory drugs. Structural features relevant to the stabilization of the newly identified inhibitors in the ATP-binding site of p38 MAPK are discussed in detail.

• Authors: Hwangseo Park, Soyoung Lee, Sungwoo Hong
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 18 Pg. 3784-7 (Sep 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26259807 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Thiazoles
• p38 Mitogen-Activated Protein Kinases

Topics

• Dose-Response Relationship, Drug
• Drug Design
• Humans
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Thiazoles (chemical synthesis, chemistry, pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)