一种抗磷酸酶的、源自L-酪氨酸的LPA1/LPA3双重拮抗剂的研发。

Development of a phosphatase-resistant, L-tyrosine derived LPA1/LPA3 dual antagonist.

作者信息

East James E, Carter Karen M, Kennedy Perry C, Schulte Nancy A, Toews Myron L, Lynch Kevin R, Macdonald Timothy L

机构信息

Department of Chemistry, University of Virginia, PO Box 400319, McCormick Road, Charlottesville, VA 22904, USA; Tel: +1-434-924-0595.

出版信息

Medchemcomm. 2011 Mar 3;2(4):325-330. doi: 10.1039/C0MD00273A.

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.

溶血磷脂酸（LPA）是一种生物活性化合物，因其在肿瘤疾病中的作用而受到关注。我们的团队开发了一种强效的LPA1/LPA3双重受体拮抗剂VPC51098（LPA1的IC(50)=84 nM，LPA3的IC(50)=48 nM），其含有一个不稳定的磷酸头部基团。这种不稳定性阻碍了我们在体内对LPA受体拮抗剂支架的评估。我们希望用一个可能更稳定的头部基团取代磷酸基团，同时保持对LPA1和LPA3的活性，以促进未来的体内研究。我们测试了所有头部基团的体外活性，包括α-亚甲基、α-氟亚甲基、α-羟亚甲基；乙烯基膦酸酯；α-氟乙烯基膦酸酯。发现最有效的化合物是低 microM 抑制剂VPC51299，其含有乙烯基膦酸酯，静脉给药时在大鼠体内的半衰期约为90分钟。在此，我们描述了这些化合物的合成及初步生物学评价。