Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 21, Issue 17, Pages 5098-5101Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2011.03.068
Keywords
Lysophospholipase D; Lysophosphatidic acid; Fluorogenic assay; Structure-activity relationship; Alpha-substituted phosphonate
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Funding
- National Institutes of Health [NS29632]
- Merck Research Laboratories
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Autotaxin (ATX) is an attractive target for the anticancer therapeutics that inhibits angiogenesis, invasion and migration. ATX is an extracellular lysophospholipase D that hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid. The aromatic phosphonate S32826 was the first described nanomolar inhibitor of ATX. However, the tridecylamide substituent on aromatic ring contributed to its poor solubility and bioavailability, severely limiting its utility in vivo. c Log P calculations revealed that the lipophilicity of S32826 could be lowered by shortening its hydrophobic chain and by introducing substituents alpha to the phosphonate. Herein, we describe the synthesis of a small set of alpha-substituted phosphonate analogs of S32826, and we show that shortening the chain and adding alpha-halo or alpha-hydroxy substituents increased solubility; however, ATX inhibition was reduced by most substitutions. An optimal compound was identified for examination of biological effects of ATX inhibition in vivo. (c) 2011 Elsevier Ltd. All rights reserved.
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