MDA5 inhibitor (Odyssey)

Phosphodiesterases (PDEs) have drawn attention due to their critical roles in physiological and pathological conditions. Many research groups have studied these hydrolytic enzymes to develop new drugs, including apremilast as a PDE4 inhibitor and sildenafil as a PDE5 inhibitor. Targeting PDE7 has also been deemed a rational strategy to ameliorate autoimmune conditions. However, to date, no successful clinical results have been reported. We postulated that progress in these studies with PDE7 had been hampered by the lack of a potent ligand with a reasonable selectivity for this PDE isozyme. Therefore, starting from a PDE7A/7B dual inhibitor, our investigations led to improved selectivity along with extended metabolic stability, resulting in a novel PDE7A inhibitor 26. This compound with high selectivity over the closest isozyme is an ideal chemical entity to unveil new pharmacological roles of PDE7A-dependent signaling, as exemplified by the in vivo antiosteoporotic effects.