Synthesis and Structure − Activity Relationship Studies of Novel Dual Inhibitors of Soluble Epoxide Hydrolase and 5 ‐ Lipoxygenase

Current research leads to the assumption that drugs affecting more than one target could result in a more efficient treatment of diseases and fewer safety concerns. Administration of drugs inhibiting only one branch of the arachidonic acid cascade is usually accompanied by side effects. We therefore designed and synthesized a library of hybrid molecules incorporating an imidazo[1,2-a]pyridine and an urea moiety as novel soluble epoxide hydrolase (sEH)/5-lipoxygenase (5-LO) dual inhibitors. Evaluation of the compounds was accomplished by in vitro testing using recombinant enzyme assays. ■ INTRODUCTION The approach “one drug−one target−one disease” was the predominant principle in drug development over decades. However, when considering treatment of complex diseases, interaction with one target may not be enough. Clinical studies on approved drugs showed that we may consider a rational design of drugs that interact with multiple targets but do not interact with off-targets responsible for side effects. These socalled designed multiple ligands (DMLs) have the advantage over combination therapies that there are fewer safety concerns because drug−drug interactions need not be considered. The arachidonic acid cascade is involved in many inflammatory processes due to the production of diverse inflammatory mediators such as prostaglandins and leukotrienes, products of the cyclooxygenase (COX) and the lipoxygenase (LOX) pathways. The 5-lipoxygenase (5-LO) is a dioxygenase that catalyzes two steps in the biosynthesis of leukotrienes which regulate the innate immune response and play a pathophysiological role in chronic inflammatory diseases such as asthma and atherosclerosis. As reviewed by Pergola and Werz, 5-LO inhibitors have been developed for over 25 years, but the only inhibitor that entered the US market yet, is Zileuton (Figure 1), a drug used for the treatment of asthma with restrictions due to its liver toxicity and a short half-life. Recent research therefore focuses on the potential of dual inhibitors such as those for prostaglandin/leukotriene synthesis. An example for this is licofelone (Figure 1), which inhibits the 5-LO activating protein (FLAP), the COX-1, and the microsomal prostaglandin E synthase-1 (mPGES-1). Besides the COX and LOX pathways, CYP enzymes also metabolize arachidonic acid to either hydroxyeicosatetraenoic acids (HETEs) or epoxyeicosatrienoic acids (EETs). The latter are further hydrolyzed by the soluble epoxide hydrolase (sEH) to their corresponding diols, the dihydroxyeicosatrienoic acids (DHETs). EETs exhibit anti-inflammatory and antihypertensive properties and have been reported to exert beneficial effects in disease models related to cardiovascular diseases, diabetes, inflammatory pain, and other indications. Both sEH−/− mice and animals treated with sEH inhibitors show an increased level of EETs and 5-LO products, indicating that sEH inhibitors might synergize with COXand 5-LO inhibitors. Co-administration of the sEH inhibitor t-AUCB (Figure 1) with either a COXor 5-LO inhibitor showed a significant enhancement of their anti-inflammatory activities. sEH inhibitors alone induced albuminuria in mice, probably due to a shift toward the 5-LO branch of the arachidonic acid cascade. Hwang et al. developed dual COX-2/sEH inhibitors and showed in a lipopolysaccharide induced mouse model that the antiallodynic activity of the dual inhibitor is more effective than either single-target inhibitor alone or the coadministration of a COX-2 and a sEH inhibitor. Therefore, the development of DMLs inhibiting both 5-LO and sEH might lead not only to highly interesting and effective anti-inflammatory compounds, but also to safer antihypertensive drugs. We synthesized hybrid molecules out of two known pharmacophores of sEH and 5-LO inhibitors to generate a tool compound for the further evaluation of this hypothesis. Received: November 2, 2012 Published: January 28, 2013 Figure 1. Known inhibitors of sEH and 5-LO. Brief Article