Characterization of a Novel Series of Endothelin-A Receptor Antagonists in the Setting of Infection Associated Preterm Birth
Nicole S. Olgun, Hardik J. Patel, Ralph Stephani, Sandra E. Reznik, College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences
Abstract: Clinically defined as any birth occurring prior to 37 weeks’ of gestation, preterm birth (PTB) accounts for approximately 13% of all live births in the United States each year and is a leading cause of infant mortality. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide which is upregulated by inflammatory cytokines and is capable of causing an increase in myometrial tone. In the setting of infection in pregnancy, ET-1 has been shown to be up-regulated, ultimately leading to PTB. In our previous work, we have shown that our novel series of 1-3-6-trisubstituted-2-carboxy-quinol-4-ones act as selective Endothelin-A receptor antagonists (ET A-RAs). In particular, HJP-272, the prototype compound, binds to the ET A receptor with an IC 50 value of 70.1nM in a non-competitive manner. We have also shown that in the animal model, HJP-286, the n-propyl analogue, and HJP-272 successfully shut down PTB. Concern for the clinical utility of these compounds as tocolytic agents is based on their potential teratogenic effects. Therefore, in the current work, we investigate whether or not there are any chronic histological changes taking place in the animal model following exposure to these agents. C57Bl/6 mice are injected with either phosphate buffered saline, vehicle(dH20 with KOH and K2CO3), or HJP-272, HJP-286 or HJP-278 (n-butyl analogue). Animals are observed for ten days and then sacrificed. All vital organs are harvested, processed, and observed using light microscopy to assess specific organ toxicity. Previous acute toxicity studies in which the animals were sacrificed after 24 hours showed no difference between control and treated animals. From these studies, we can conclude that not only do our compounds have a high affinity for the ET A receptor, but they also prevent PTB at doses in which we see no toxicity in the mother. It is our hope that these compounds may one day affect the way pregnant women presenting with PTB are treated, as there is currently no FDA approved therapy for this very important clinical disorder.