title: Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist.
abstract: Lysophosphatidic acid (LPA) is a bioactive compound that has gained attention due to its role in neoplastic diseases. Our group has developed a potent dual LPA1/LPA3 receptor antagonist, VPC51098 (LPA1 IC(50) = 84 nM, LPA1 IC(50) = 48 nM) that contained a labile phosphate head group. This lability has impaired our evaluation of our scaffold of LPA receptor antagonists in vivo. We wished to replace the phosphate with a potentially more stable head group while retaining potency at both LPA1 and LPA3 to facilitate future in vivo studies. We tested in vitro potency of all head groups including α-methylene, α-fluoromethylene, α-hydroxymethylene; vinyl phosphonates; α-fluoro vinyl phosphonates. The most potent compound was found to be a low micromolar inhibitor VPC51299 that contained a vinyl phosphonate and possessed a half-life of approximately 90 min in rats when dosed intravenously. Herein, we describe the synthesis and initial biological evaluation of these compounds.
authors.affiliation: Department of Chemistry, University of Virginia, PO Box 400319, McCormick Road, Charlottesville, VA 22904, USA; Tel: +1-434-924-0595.
authors.forename: James E
authors.initials: JE
authors.lastname: East
authors.forename: Karen M
authors.initials: KM
authors.lastname: Carter
authors.forename: Perry C
authors.initials: PC
authors.lastname: Kennedy
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Schulte
authors.forename: Myron L
authors.initials: ML
authors.lastname: Toews
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Macdonald