A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea

A series of dual inhibitors containing a 1,5-diarylpyrazole and a urea were designed, synthesized, and evaluated as novel COX-2/sEH dual inhibitors using recombinant enzyme assays and using a lipopolysaccharide (LPS) induced model of pain in rats. COX and LOX enzymes seems advantageous in various cardiovascular diseases and malignancy therapy.3 Several dual 781658-23-9 supplier inhibitors4 that inhibit cyclooxygenases (either COX-2 or both COX-1 and COX-2) and 5-LOX have been reported as potential agents for the treatment of arthritis. Licofelone (ML-3000) is an example of such an arthritis drug.5 And such dual inhibitors also have been prepared to treat inflammation,6 pain,7 and cancers.8 In addition to the COX and Rabbit polyclonal to AKT2 LOX pathways, there is a third major metabolic pathway in the AA cascade involving cytochrome P450 metabolism. This pathway prospects to the formation of 20-hydroxyeicosatetranoic acid (20-HETE)9 and arachidonic acid monoepoxides known as epoxy-eicosatrienoic acids (EETs).10 The soluble epoxide hydrolase (sEH) enzyme catalyzes the conversion of these EETs into the corresponding diols, or dihydroxyeicosatrienoic acids (DHETs). EETs are known to exhibit vasodilatory,11 cardioprotective,12 anti-inflammatory,13 and anti-hyperalgesic14 properties, while the 781658-23-9 supplier DHETs have greatly reduced activity in most assays.15 NSAIDs target cyclooxygenases which are key enzymes involved in prostaglandin (PG) biosynthesis from AA.16 However, morbidity and mortality due to NSAID-induced gastrointestinal (GI) toxicity are so significant and frequent worldwide to limit the therapeutic use of this drug class.17 To mitigate this side effect caused 781658-23-9 supplier primarily by COX-1 inhibition, COX-2 selective inhibitors, or coxibs such as celecoxib and rofecoxib, were designed and developed. These coxibs were specialized to retain the beneficial anti-inflammatory and anti-hyperalgesic properties of NSAIDs but enhance GI tolerance.18 In spite of this design, COX-2 selective inhibitors maintain some GI toxicity at higher doses and/or with long-term use. Moreover, COX-2 selective inhibitors may drop selectivity and inhibit COX-1 at higher doses, resulting in the undesirable side effects.19 High doses of COX-2 selective inhibitors also shift plasma thromboxane/prostacyclin ratio20,22 and increase the eicosanoid 20-HETE, which could potentially lead to thrombic events and hypertension.21 We have previously demonstrated that drug combinations with low doses of NSAIDs and soluble epoxide hydrolase inhibitors (sEHIs) produce synergistic effects when measuring anti-hyperalgesia and anti-inflammation outcomes. This observed sEHI synergy with NSAIDS reduces pain and inflammation while prospectively decreasing the side effects of coxibs such as cardiovascular toxicity.22 In general, there are security issues when administering combination therapy. Two drugs which are safe when used independently of each other cannot be assumed to be safe in combination, as drug-drug conversation warnings indicate. There are several tests that are necessary to find the optimal dose regiments including security studies, a complex dosage ranging investigation, and drug-drug conversation analysis, all of which may significantly raise the practical cost and complexity of developing combination therapies.23 It is clear that this issue is also not exclusively due to metabolic shunting effects. For drug development, the prediction of pharmacodynamic and pharmacokinetic associations is substantially less complex if polypharmacological action is derived from a single agent rather than from combination therapies (co-administration). Therefore, there has recently been a growing desire for designed multiple ligands (DMLs).24 The aim of DMLs is to enhance drug efficacy and improve drug safety by acting specifically on multiple targets (targeted polypharmacology), as opposed to drugs that address only a single target. DMLs have advantages over combination drugs or combination therapies because they circumvent the inherent problems associated with formulation of two or more drugs utilized for co-administration. In addition, the distinct differences in the pharmacodynamic and pharmacokinetic properties of individual drugs which may raise safety issues, do not apply to DMLs.25 DMLs may also offer some advantage due to regulation of intellectual property. For all of these reasons dual inhibition of COX-2 and sEH through a single molecule is likely to be more advantageous than co-administration of the drugs using combination therapy. The therapeutic targeting.