Blockade of endothelin-1 with a novel series of 1,3,6-trisubstituted-2-carboxy-quinol-4-ones controls infection-associated preterm birth.
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 (ET(A)) receptor with either BQ-123 or with HJP-272, the 6-OH compound of our series of novel synthetic (ET(A)) receptor antagonists. In the current study, we show that HJP-272, a highly selective ET(A) receptor antagonist with an IC(50) of 70.1 nmol/L, binds in a noncompetitive manner to the ET(A) receptor. Additionally, we introduce n-propyl (HJP-286) and n-butyl (HJP-278) analogs of HJP-272. We find that the LD(50) 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.
Olgun
Nicole S
NS
College of Pharmacy and Allied Health Professions, St John’s University, Jamaica, New York 11439, USA.
Patel
Hardik J
HJ
Stephani
Ralph
R
Lengyel
Istvan
I
Reznik
Sandra E
SE
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D052117:Benzodioxoles / Q000627:therapeutic use*; D001667:Binding, Competitive; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006912:Hydroxyquinolines / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000517:prevention & control*; D011270:Pregnancy, Animal; D047928:Premature Birth / Q000209:etiology* / Q000517:prevention & control*; D015363:Quinolones / Q000627:therapeutic use*; D044022:Receptor, Endothelin A / Q000378:metabolism; D013552:Swine
C532839:3-(3-carboxybenzyl)-1-((6-ethylbenzo(d)(1,3)dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid; D052117:Benzodioxoles; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; C556440:HJP 278; C556441:HJP 286; D006912:Hydroxyquinolines; D008070:Lipopolysaccharides; D015363:Quinolones; D044022:Receptor, Endothelin A; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes
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