Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist.
Medchemcomm
; 2(4): 325-330, 2011 Mar 03.
Article
in En
| MEDLINE
| ID: mdl-22180836
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Medchemcomm
Year:
2011
Document type:
Article