Hypoxia-Activated Prodrugs with Dual COX-2/CA Inhibitory Effects on Attenuating Cardiac Inflammation under Hypoxia

Cardiac inflammation is generally
accompanied by hypoxia,
while
myocardial injury and an abnormal microenvironment caused by hypoxia
tend to suppress the efficacy of common anti-inflammatory drugs. To
improve the anti-inflammatory effect under hypoxia, a hypoxia-activated
prodrug HAP1 consisting of a cyclooxygenase-2 (COX-2) inhibitor Ind
and a carbonic anhydrase (CA) inhibitor Ace was synthesized. HAP1
was found to be activated by nitroreductase (NTR) under hypoxia to
release two pharmacophores and achieve the combinatory medication
intensively at the hypoxic site, better than Ind or Ace alone. When
NTR activity was inhibited by Na2WO4 under hypoxia,
no pharmacophores were found to release from HAP1 without exhibiting
its activity. However, the efficacy of the Ind and Ace combination
group (I&A) was not affected. Furthermore, HAP1 showed advantages
over I&A in vivo not only in improving bioavailability but also
in reducing side effects. The HAP approach turns out to inhibit cardiac
inflammation efficiently and safely under hypoxia.