Sandra E.Reznik
The Effect of
3-(3-Carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic
acid (HJP279), a Putative Novel Selective ETA Receptor Antagonist
(ETA-RA), on Infection-Mediated Premature Delivery
Sandra E. Reznik, Department of Pharmaceutical Sciences,
College of Pharmacy and Health Sciences
Nicole Olgun and Hardik J. Patel, St.
John’s University Students
Ralph Stephani, Department of
Pharmaceutical Sciences, College of Pharmacy and Allied Health
Professions
Wei Wang and Haoting Yen, Graduates of
St. John's University
Abstract: Premature delivery,
defined as delivery before 37 weeks’ gestation, now occurs in 12%
of all births, and accounts for nearly half of long-term
neurological morbidity. Current therapeutic approaches to
preterm delivery are ineffective and present serious risks to both
the mother and fetus. Although multiple factors lead to
premature delivery, the single most common cause is
infection. Previous in vitro investigations have shown that
endothelin-1 (ET-1) is induced by inflammatory cytokines and that
it increases 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 inhibition of ET-1 synthesis through the
use of the metalloproteinase inhibitor phosphoramidon, blockade of
ET-1 action with the established selective ETA-RA BQ-123 and
silencing of the endothelin-converting enzyme-1 (ECE-1) gene with
ECE-1 RNAi all result in control of preterm labor. In the current
work, we show that blockade of ET-1 action with 50 mg/kg
intraperitoneal (ip)
3-(3-carboxybenzyl)-1-((6-ethylbenzo[d][1,3]dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic
acid (HJP279), a putative novel selective ETA-RA (IC50 70 nM),
synthesized by RS and HJP, prevents PTB induced with 50 mg/kg of ip
lipopolysaccharide in a mouse model. The ability to control
premature delivery by antagonizing or silencing the ECE-1/ET-1
system suggests a novel approach to a very important, longstanding,
unmet clinical need.