Blockade of endothelin-1 with a novel series of 1,3,6-trisubstituted-2- carboxy-quinol-4-ones controls infection-associated preterm birth

Abstract

Preterm birth (PTB) currently accounts for 13% of all births in the United States, with the leading cause of PTB being maternal infection. Endothelin-1, an extremely potent vasoconstrictor capable of increasing myometrial smooth muscle tone, has been shown to be up-regulated in the setting of infection in pregnancy, ultimately leading to PTB. In previous work, we have shown that infection-associated PTB is controlled in our murine model by using phospharamidon, an endothelin-converting enzyme-1 inhibitor; knocking down endothelin-converting enzyme-1 mRNA; or blocking the binding of endothelin-1 to the endothelin-A (ETA) receptor with either BQ-123 or with HJP-272, the 6-OH compound of our series of novel synthetic (ETA) receptor antagonists. In the current study, we show that HJP-272, a highly selective ETA receptor antagonist with an IC50 of 70.1 nmol/L, binds in a noncompetitive manner to the ETA receptor. Additionally, we introduce n-propyl (HJP-286) and n-butyl (HJP-278) analogs of HJP-272. We find that the LD50 of HJP-272, the analog in the series most effective in controlling preterm birth, is more than 20-fold higher than its therapeutic dose. Acute exposure to high doses of these compounds produces no histological changes in any organ, while chronic exposure produces only a rare hepatotoxic effect. These findings may be of clinical significance, as there is currently no FDA-approved therapy for women presenting with threatened preterm delivery. Copyright © American Society for Investigative Pathology.