Development and therapeutic potential of NOSH‐NSAIDs: A new class of anti‐inflammatory pharmaceuticals

Abstract

Non‐steroidal anti‐inflammatory drugs (NSAIDs) are mainly used to treat pain, reduce fever and inflammation; some also have utility as anti‐platelet agents. There is also a large body of data supporting the notion that NSAIDs are important for cancer prevention. However, their long‐term use is problematic on two accounts: (1) suboptimal efficacy, which is less than 50% and (2) side effects including gastrointestinal, cardiovascular, and renal, which precludes their widespread use. In our search for a “better NSAID”, we developed NOSH‐NSAIDs. These are regular NSAIDs such as aspirin, naproxen, sulindac and others to which nitric oxide (NO) and hydrogen sulfide (H2S) releasing moieties have been covalently attached. Both NO and H2S are gaseous signaling molecules of biological importance. The rational for incorporating these gaseous mediators into NSAID molecules was based on the observations that NO and H2S have some of the same properties as prostaglandins within the gastric mucosa, thus modulating some components of the local mucosal defense systems which should lead to reduced gastrointestinal toxicity and also should embark enhanced cardiovascular and renal safety profiles because NO and H2S have protective roles in the cardiovascular and renal systems. To date we have reported on the synthesis and some general characterizations of three such compounds. NOSH‐aspirin (NBS‐1120), NOSH‐naproxen (AVT‐219), and NOSH‐sulindac (AVT‐18A) have enhanced GI profiles yet they retain all the basic pharmacological activities of their respective native NSAID. Furthermore, we have also reported that these compounds are orders of magnitude more potent than their corresponding NSAID in inhibiting the growth of adenomatous, epithelial, and lymphocytic cancer cell lines, thus demonstrating a generalized property that was tissue‐type independent. In vivo, NBS‐1120 was shown to have chemo‐preventive properties that were superior to aspirin and AVT‐219 was shown to have chemotherapeutic properties. Of interest is also the observation that NBS‐1120 showed synergistic activity with 5‐flurouracil, an established chemotherapeutic agent, in inhibiting colon cancer cell growth. Encouraged by our initial observations, we have formed a company, Avicenna Pharmaceuticals, Inc., around this technology and have forged a path towards an IND application and phase‐1 clinical trials, hopefully to bring these compounds into the clinic.