Naproxcinod is the first in the class of CINODs and has been evaluated in preclinical and clinical studies. It is metabolized to naproxen and has been shown to donate nitric oxide in vitro and in vivo. It stimulated the expression of heme oxygenase-mRNA in endothelial cells in vitro, a crucial mediator of antioxidant and tissue-protective actions. In preclinical studies, Naproxcinod has been shown to be analgesic and anti-inflammatory. Naproxcinod dose-dependently displayed a noticeable and significant anti-ischemic effect in reperfused ischemic rabbit hearts and did not exhibit the hypertensive effects of naproxen. In a proof of concept study in 31 healthy volunteers with GI tolerance as the primary endpoint, Naproxcinod caused fewer gastric erosions in both the stomach and the duodenum than naproxen, while 0.2 erosions were found with placebo. Naproxcinod caused less of an adverse effect in intestinal permeability than naproxen and was similar to placebo.