Synthesis and structure-activity relationships of tyrosine-based inhibitors of autotaxin (ATX)

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:20

Article

East, James E.¹  Kennedy, Andrew J.¹  Tomsig, Jose L.²  De Leon, Alexandra R.²  Lynch, Kevin R.²  Macdonald, Timothy L.^1,2 

[1] Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA

[2] Univ Virginia, Dept Pharmacol, Charlottesville, VA 22908 USA

关键词: Lysophosphatidic acid;    Autotaxin;    Structure-activity relationships;    Hansch linear free energy relationship;   

DOI  :  10.1016/j.bmcl.2010.09.030

来源: Elsevier

【 摘 要 】

Autotaxin (ATX) is a secreted soluble enzyme that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Because of LPA's role in neoplastic diseases, ATX is an attractive therapeutic target due to its involvement in LPA biosynthesis. Here we describe the SAR of ATX inhibitor, VPC8a202, and apply this SAR knowledge towards developing a high potency inhibitor. We found that electron density in the pyridine region greatly influences activity of our inhibitors at ATX. (C) 2010 Elsevier Ltd. All rights reserved.

【 授权许可】

Free