New approach in the treatment of inflammation: development of 5-LOX/sEH dual inhibitors and their pharmacological characterization (NAIDI)- PRN2022 PNNR

Despite anti-inflammatory drug discovery is very intensive, inflammatory diseases remain among the most serious health burdens and the medical need for more potent and safe anti-inflammatory drugs still remains. Moreover, despite the number of druggable inflammatory targets constantly grows, especially in the most severe disorders, innovative agents usually fail to attain therapeutic efficacy. This is probably due to the wide use of the one target–one drug approach that proven not to be a reliable approach in this context. In fact, inflammation is a very complex pathophysiological process, involving a myriad of enzymes, mediators, and receptors, producing proinflammatory agents as well as resolvins. Therefore, pharmacological modulation of a single target tends to generate shunting phenomena that can compromise therapeutic efficacy. This is why, robust anti-inflammatory therapies often involve the use of multiple drugs, but considering the drawbacks of polypharmacy, a multitarget polypharmacological approach appears to be more suitable. On the other hand, polypharmacology usually relies on serendipity discovery and aprioristic knowledge of the involved targets. This is an inherent limit to the rational design of truly innovative multitarget molecules and the reason why the polypharmacology approach in drug design should be supported by cutting-edge technologies to highlight all the different pathways responsible for the multitarget drug effect in a complex biological system. Therefore, polypharmacology needs in-depth analyses of complex pathological pathways using disruptive omics technologies. In particular, metabolomics recently revealed its dramatic potential in this context. Researchers from the research consortium responsible for the present project have recently identified an indoline-based compound as dual 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH) inhibitor. The molecule showed good efficacy when challenged in vitro, also showing remarkable in vivo effects, despite its poor pharmacokinetic properties (Compound 73, Figure 1). Therefore, this molecule represents an interesting hit compound for a hit-to-led development medicinal chemistry campaign aimed to the preclinical development of dual 5-LOX/sEH inhibitor as anti-inflammatory agents. The project will be based on three different tasks: 1) rational design and synthesis of compound new analogues of compound 73 to be screened for their enzymatic inhibitory efficacy and their in vitro pharmacokinetic properties; 2) In vivo testing of selected compounds in mouse model of pancreatitis and peritonitis along with the in vivo pharmacokinetic assessments; 3) metabolomic analyses on biofluids, tissues and cells to shed light about the modulated molecular targets.