Drug Discovery Opinion

Selective cyclooxygenase-2 (COX-2) inhibitors were developed to reduce the risk of gastrointestinal side effects associated with the older non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit both COX-1 and COX-2. The withdrawal of rofecoxib (Vioxx™) in 2004 and valdecoxib (Bextra™) in 2005 because of a slightly increased risk of thrombotic events such as heart attacks and strokes after long-term treatment came as a blow to the pharmaceutical industry, doctors and patients. Since the withdrawal of rofecoxib and valdecoxib, no new anti-inflammatory drugs have been submitted to the FDA for the treatment of osteoarthritis.

Last month, however, French pharmaceutical company, NicOX, submitted an NDA for its first-in-class cyclooxygenase-inhibiting nitric oxide donator (CINOD), naproxcinod, for the treatment of osteoarthritis.

Naproxcinod is a nitroxybutyl ester of the well established and well tolerated NSAID, naproxen, and is intended to overcome another drawback of NSAIDs and COX-2 inhibitors – increased blood pressure. Cleavage of naproxcinod by esterases gives naproxen, together with a nitric oxide donating moiety. Nitric oxide relaxes vascular smooth muscle cells, causing dilation of the arteries and reducing blood pressure, and has also been reported to reduce formation of thrombi. In clinical trials in patients with osteoarthritis of the knee and hip, naproxcinod met efficacy endpoints and did not cause an increase in blood pressure. Naproxcinod also showed an advantage compared with naproxen in terms of gastrointestinal side effects.

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