Discovery\nof a Phosphodiesterase 7A Inhibitor of High\nIsozyme Selectivity Exhibiting <i>In Vivo</i> Anti-Osteoporotic\nEffects

Phosphodiesterases (PDEs) have drawn attention due to\ntheir critical\nroles in physiological and pathological conditions. Many research\ngroups have studied these hydrolytic enzymes to develop new drugs,\nincluding apremilast as a PDE4 inhibitor and sildenafil as a PDE5\ninhibitor. Targeting PDE7 has also been deemed a rational strategy\nto ameliorate autoimmune conditions. However, to date, no successful\nclinical results have been reported. We postulated that progress in\nthese studies with PDE7 had been hampered by the lack of a potent\nligand with a reasonable selectivity for this PDE isozyme. Therefore,\nstarting from a PDE7A/7B dual inhibitor, our investigations led to\nimproved selectivity along with extended metabolic stability, resulting\nin a novel PDE7A inhibitor <b>26</b>. This compound with high\nselectivity over the closest isozyme is an ideal chemical entity to\nunveil new pharmacological roles of PDE7A-dependent signaling, as\nexemplified by the <i>in vivo</i> antiosteoporotic effects.