Medicinal Chemistry, 2007, 3, 433-438 433 1573-4064/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. 6-Aryl-4-Oxohexanoic Acids: Synthesis, Effects on Eicosanoid Biosynthesis, and Anti-Inflammatory In Vivo-Activities Khaled Abouzid 1,2,* , Petra Frohberg 3 , Jochen Lehmann 2 and Michael Decker 2,* 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 2 Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Jena, Germany; 3 Institut für Pharmazie, Pharmazeutische Chemie, Martin-Luther Universität Halle-Wittenberg, Halle, Germany Abstract: The synthesis of a series of 6-aryl-4-oxohexanoic acids is described: This involves condensation of an appro- priate aldehyde (Ia-f) and levulenic acid using catalytic amounts of piperidine and acetic acid in toluene to afford the 6- aryl-4-oxohex-5-enoic acids (IIa-f).The arylidene derivatives (IIa-d) were reduced by hydrogen at room temperature us- ing palladium (10 %/carbon) as catalyst to produce 6-aryl-4-oxohexanoic acids (IIIa-d) as target compounds. In certain instances, the lactone derivative (IVd) was obtained as a low-melting by-product. These compounds were tested in two models used for evaluating the activity of non-steroidal anti-inflammatory drugs (NSAIDs). The first test is the effect of the synthesized compounds on arachidonic acid metabolism in vitro using human whole blood assay. The second is the in vivo carrageenan induced rat paw edema test. Compound IIe showed higher in vivo-activity compared to fenbufen at the same dose level (50mg/kg). Key Words: 6-Aryl-4-oxohexanoic acids, Inflammation, NSAIDs, rat paw edema test, 5-lipoxgenase, arachidonic acid metabo- lism. INTRODUCTION Non-steroidal anti-inflammatory drugs (NSAIDs) are a widely prescribed and applied class of medications with es- tablished anti-inflammatory, analgesic, and antipyretic prop- erties [1,2]. Despite these benefits, traditional NSAIDs such as (2-acetyloxy)benzoic acid, propionic or acetic acid deriva- tives have significant gastrointestinal (GI) toxicity as they inhibit both COX-1 and COX-2 isoforms and frequently cause gastrointestinal irritations or excessive bleeding [3-5]. These negative side effects prompted the development of selective COX-2 inhibitors as promising gastroprotective agents [6,7]. Many of these agents have been developed and marketed such as celecoxib and refecoxib, which have been extensively studied and showed exceptional anti-inflamma- tory properties with reduced GI toxicity. Later on, some po- tential limitations of long term certain COX-2 inhibitor ther- apy were described including ulcer exacerbation in high-risk patients, delayed gastroduodenal ulcer healing, thrombosis due to prostacyclin deficiency and kidney toxicity. Thus COX-2 inhibitors have not eliminated the need for improved drugs in the NSAID area [8-11]. In an important report [12], the effect of some selective COX-2 inhibitors and some dual (COX-1 and COX-2) inhibitors on carrageenan pleurisy in the rat over a time period ranging from 0 to 48 h after injection of the irritant was studied. The result of this study showed that the COX-2 inhibitors confered anti-inflammatory activity early in the inflammatory response, coincident with the expression of COX-2 protein as did the older dual inhibitors such as indomethacin. However, by 6 h the COX-2 inhibitors were *Address correspondence to these authors at the Lehrstuhl für Pharmazeuti- sche/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller- Universität Jena, Jena, Germany; E-mail: m.decker@uni-jena.de; abouzid@yahoo.com without effect although the dual inhibitors still showed efficacy. At this point the COX-2 protein as shown by Western blotting was no longer present. This study showed the supremacy of conventional NSAIDs over the COX-2 inhibitors for chronic use. Moreover, withdrawal of rofecoxib from market recently by its originators due to adverse cardiovascular effects puts a question mark on the safety profile of other COXIBs in the long-term therapy. Attempts to develop alternative COX-2 inhibitors by slight modification of the classical NSAIDs, resulted in dis- covery of lumiracoxib [13], a close structural analog to the well-known NSAID, diclofenac. Recently, a new approach of anti-inflammatory therapy constitutes the use of inhibitors of COX-1/2 and LOX pathways as an attempt to develop new active leads which may provide novel NSAIDs [14-17]. RATIONAL AND DESIGN In the present work, and in continuing efforts to find dis- tinctive structural template to NSAIDs with a wider safety margin, we reinvestigated many of the traditional carboxylic acid NSAIDs in order to design modified new leads en- dowed with possible potent and dual COX-1/2 and LOX inhibitory activity. We utilized the -oxobutanoic acid struc- tural moiety with suitable substitution at the phenyl ring as structural template to the leads, since it was reported earlier, that arylhexenoic acids possess only weak anti-inflammatory activity in paw oedema test. Therefore, we became interested in synthesizing modified congeners in attempts to improve their activity [18]. To accomplish this goal, we designed a novel series of compounds with aliphatic carboxylic acid side chain in which 2 carbon spacer linker was used as a connection unit between the ketonic group of oxobutanoic acid and the aryl group mimicking certain NSAIDs such as fenbufen [19], bucloxic acid [20], and trepibutone [21], re- spectively. This linker could be an ethylene as in case or