title: Aromatic phosphonates inhibit the lysophospholipase D activity of autotaxin.
abstract: 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. cLogP 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 α-substituted phosphonate analogs of S32826, and we show that shortening the chain and adding α-halo or α-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.
authors.affiliation: Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, UT 84108-1257, USA.
authors.forename: Guowei
authors.initials: G
authors.lastname: Jiang
authors.forename: Damian
authors.initials: D
authors.lastname: Madan
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Prestwich
mesh_terms: D001682:Biological Availability; D063065:Organophosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism; D000099189:Lysophospholipase D
chemical_list: D063065:Organophosphonates; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D