NO-donors (VII [1]): Synthesis and cyclooxygenase inhibitory properties of N- and S-nitrooxypivaloyl-cysteine derivatives of naproxen - A novel type of NO-NSAID

Article abstract of DOI:10.1002/1521-4184(200211)335:8<363::AID-ARDP363>3.0.CO;2-S

Nitric oxide (NO) has been reported to subserve many of the same mucosal protection mechanisms as prostaglandins and is sufficient for acute gastroprotection and ulcer healing. In fact, NO-donating NSAID hybrid compounds such as the nitrooxybutyl ester of naproxen show reduced ulcerogenic activity while maintaining anti-inflammatory activity. We introduce two prototypes of novel triple-hybrid compounds consisting of cysteine which is known to enhance the activity of organic nitrates and to reduce nitrate tolerance, an NSAID (naproxen), and an organic nitrate (nitrooxypivaloic acid). L-Cysteine ethyl ester first was N-acylated in a CH₂Cl₂/H₂O two-phase system using the acid chlorides of naproxen or nitrooxypivaloic acid, respectively, and sodium acetate, or alternatively using the DCC-activated nitrooxy acid in absolute CH₂Cl₂. The N-acylated intermediates were subsequently S-acylated using the acid chlorides or alternatively the carbonyldiimidazole (CDI)-activated acids again. The two naproxen-cysteine-nitrate hybrid prodrugs were screened in vitro for their cyclooxygenase inhibitory properties relative to naproxen. In this screening the N-nitrooxyacylcysteine derivative was found to be inactive in the concentration range of 0.1-10 μmol/L against both COX-1 and COX-2, while the S-nitrooxyacylcysteine derivative had only weak activity against COX-1.