Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery.

Abstract

Preterm birth (PTB), defined as any birth occurring before 37 weeks of gestation, occurs in only 12% of all births, yet accounts for nearly half of long-term neurological morbidity, and 60%-80% of perinatal mortality. The single most common cause of PTB is intrauterine infection. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide that is both upregulated by inflammatory cytokines and capable of increasing myometrial smooth muscle tone. We hypothesized, therefore, that ET-1 is a critical component of the parturition cascade in the setting of infection-associated PTB. In our previous work, we have shown that blockade of ET-1 synthesis through the use of the metalloproteinase inhibitor phosphoramidon results in control of preterm labor. In the current work, we showed that blockade of ET-1 action with 5-50 mg/kg i.p. 3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (HJP272), a putative novel selective ETA-receptor antagonist (IC50, 70 nmol/L), prevents PTB induced with up to 50 mg/kg of i.p. lipopolysaccharide in a mouse model. This is the first report, to our knowledge, of control of infection-associated PTB with a specific ETA-receptor antagonist. The identification of a novel effective therapy for PTB could have important clinical implications.

• Authors: Nicole Olgun, Hardik J Patel, Ralph Stephani, Wei Wang, Haoting Yen, Sandra E Reznik
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) Vol. 86 Issue 8 Pg. 571-5 (Aug 2008) ISSN: 0008-4212 [Print] Canada
• PMID: 18758506 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 3-(3-carboxybenzyl)-1-((6-ethylbenzo(d)(1,3)dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Hydroxyquinolines
• Lipopolysaccharides
• Receptor, Endothelin A
• Receptor, Endothelin B

Topics

• Animals
• Binding, Competitive (drug effects)
• Endothelin A Receptor Antagonists
• Endothelin B Receptor Antagonists
• Female
• Hydroxyquinolines (pharmacology)
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Inbred C57BL
• Pregnancy
• Pregnancy Complications, Infectious (prevention & control)
• Premature Birth (chemically induced, etiology, prevention & control)
• RNA Interference
• Receptor, Endothelin A (metabolism)
• Receptor, Endothelin B (metabolism)