Studies On Design, Synthesis And Anti-inflammatory Activity Of α-Substituted ρ-Methylsulfonylphenylpropenoic Acid And Related Compounds

Inflammation is a very complicated pathophysiological process, in which many inflammatory mediators are involved. Nonsteroidal anti-inflammatory drugs (NSAIDs) block the synthesis of inflammatory mediators, such as prostaglandins (PGs), leukotrienes (LTs), etc, to exert anti-inflammatory, analgesic and antipyretic activities. NSAIDs are among the most widely used prescribed drugs. However, side effects associated with NSAIDs limit their usage. Epidemiology survey suggested that 25% NSAIDs users suffer from gastrointestinal (GI) tract side effects, and 15%~20% long-term users have severe GI complications, which included ulcer, bleeding and perforation. In the United States, people who die annually from NSAIDs-induced GI lesions amount to 16500. The cost of treating GI side effects exceeds $4 billion every year. As a consequence, GI lesions not only harm people's health and increase mortality, but also greatly enlarge medical expenses. In China, the situation is basically similar to that in the US. The main reason why NSAIDs result in GI damage is that the synthsis of beneficial PGs in GI tract is inhibited while NSAIDs block the form of PGs at the site of inflammation. So reducing NSAIDs-induced GI lesions is recently one of the major challenging task of developing novel NSAIDs. Base on the progress on NSAIDs study, a series of α-substituted p-methylsulfonylphenylpropenoic acid compounds (I-V) have been designed and synthesized by applying the basic theories of drug design and the means of computer aided drug design. Their anti-inflammatory activity against xylene-induced mice ear swelling and carrageenin-induced rat paw edema was biologically evaluated, and their GI side effects in the rats were examined. On the basis of biology results, the structure-activity relationships (SARs) were studied in order to obtain some useful information for further developing novel NSAIDs with stronger anti-inflammatory activity but less GI side effects. This dissertation consists of five parts as follows: Part One The status quo and prospect of NSAIDs This part reviews several inflammatory mediators and progress on current NSAIDs research, including cyclooxygenase-2 (COX-2) selective inhibitors, COX/5-Lipoxygenase (5-LO) dual inhibitors, nitric oxide-releasing NSAIDs (NO-NSAIDs), cytokine inhibitors, etc. The prospect of future NSAIDs is also presented. Part Two Design So far most COX-2 selective inhibitors structurally belong to tricyles. They are characterized by a moiety of cis-stilbene with a functional group p-methylsulfonyl or p-aminosulfonyl in one of the aryls. It was also reported that some trans-phenylpro-penoic acid derivatives were COX/5-LO dual inhibitors. On the basis of computer aided drug design, a series of α-substituted p-methylsulfonylphenylpropenoic acid (I) were designed by combining the feature structure of trans-phenylpropenoic acid and Rofecoxib, a tricycle type of COX-2 selective inhibitor which entered market in 1999. NO-NSAIDs (II) were synthesized by coupling I and NO donors; III were obtained by conversion of I to amides in order to increase COX-2 selective activity; IV were formed by conversion of I to hydroxamic acids in order to gain COX/5-LO dual inhibitory properties. V were designed by replacement of 3,5-di-tert-butyl-4-hydroxy-phenyl in the structure of some COX/5-LO dual inhibitors by p-methylsulfonylphenyl which is a key pharmacophore of COX-2 selective inhibitors. We expect these targetcompounds exhibit stronger anti-inflammatory activity and less GI side effects. Part Three Chemistry Sixty-seven target compounds (I-V), 5 byproducts (VI) and two positive controls (Rofecoxib and CI-1004) were synthesized. Seventy of them were novel compounds, whose structures were determined by IR, 1HNMR, MS and elemental analysis. Many efforts were made to synthsize and optimize the synthetic procedures of target compounds and to study the mechanism by which some byproducts formed. For example, in preparation of II, I1, 3, 13, 15, 16 reacted respectively with alcohol 57 in the presence of dicyclohexyl...