Design and synthesis of novel PDE4 inhibitors as potential candidates for antidepressant agents

PDE4 inhibitors exhibit anti-stress and antidepressant-like abilities by catalyzing the hydrolysis of cAMP, a primary regulator for intracellular communication in the brain. Herein, novel diarylpyrazole derivatives are synthesized and investigated for their ability to inhibit PDE4. In vitro studies indicate that most of the synthesized compounds show significant potency for the inhibition of PDE4. Specifically, N-(4-(3-(3,5-dimethoxyphenyl)-1 H-pyrazol-5-yl)benzyl)-2-morpholinoethan-1-amine exhibits the most potent PDE4 inhibition, with an IC 50 value of ca. 0.09 μM. It also produces antidepressant-like activities in sugar water consumption and in forced swimming tests in vivo.