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NO‐Donors (VII [1]): Synthesis and Cyclooxygenase Inhibitory Properties of N ‐and S ‐Nitrooxypivaloyl‐cysteine Derivatives of Naproxen — A Novel Type of NO‐NSAID
Author(s) -
Kartasasmita Rahmana E.,
Laufer Stefan,
Lehmann Jochen
Publication year - 2002
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(200211)335:8<363::aid-ardp363>3.0.co;2-s
Subject(s) - naproxen , chemistry , cysteine , cyclooxygenase , prodrug , nitric oxide , stereochemistry , biochemistry , organic chemistry , enzyme , medicine , alternative medicine , pathology
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 CH 2 Cl 2 /H 2 O twophase system using the acid chlorides of naproxen or nitrooxypivaloic acid, respectively, and sodium acetate, or alternatively using the DCC‐activated nitrooxy acid in absolute CH 2 Cl 2 . 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.