Synthesis and pharmacological evaluation of second-generation phosphatidic acid derivatives as lysophosphatidic acid receptor ligands.
Bioorg Med Chem Lett
; 16(3): 633-40, 2006 Feb.
Article
em En
| MEDLINE
| ID: mdl-16263282
ABSTRACT
Short-chain phosphatidic acid derivatives, dioctanoyl glycerol pyrophosphate (DGPP 80, 1) and phosphatidic acid 80 (PA 80, 2), were previously identified as subtype-selective LPA(1) and LPA(3) receptor antagonists. Recently, we reported that the replacement of the phosphate headgroup by thiophosphate in a series of fatty alcohol phosphates (FAP) improves agonist as well as antagonist activities at LPA GPCR. Here, we report the synthesis of stereoisomers of PA 80 analogs and their biological evaluation at LPA GPCR, PPARgamma, and ATX. The results indicate that LPA receptors stereoselectively interact with glycerol backbone modified ligands. We observed entirely stereospecific responses by dioctyl PA 80 compounds, in which (R)-isomers were found to be agonists and (S)-isomers were antagonists of LPA GPCR. From this series, we identified compound 13b as the most potent LPA(3) receptor subtype-selective agonist (EC(50)=3 nM), and 8b as a potent and selective LPA(3) receptor antagonist (K(i)=5 nM) and inhibitor of ATX (IC(50)=600 nM). Serinediamide phosphate 19b was identified as an LPA(3) receptor specific antagonist with no effect on LPA(1), LPA(2), and PPARgamma.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Fosfatídicos
/
Inibidores de Fosfodiesterase
/
Receptores de Ácidos Lisofosfatídicos
Tipo de estudo:
Evaluation_studies
Limite:
Animals
Idioma:
En
Revista:
Bioorg Med Chem Lett
Ano de publicação:
2006
Tipo de documento:
Article