Efforts to directly inhibit phosphodiesterase-4's active site to treat neurological indications have failed due to dose-limiting toxicities. Tetra Discovery Partners LLC is trying to take side effects out of the equation with allosteric inhibitors of PDE-4 and has preclinical programs in depression and cognitive impairment.

PDE-4 degrades cyclic AMP (cAMP), a signaling molecule that activates metabolic pathways in response to signaling by glucagon. Prior to phosphorylation, the enzyme has about 20% activity compared with the phosphorylated version.