Structure Based Design of PDE4 Allosteric Modulators

Phosphodiesterase type 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. However, the development of PDE4 therapeutics has been difficult because of well characterized dose limiting side effects in animal models and in human clinical trials. We have obtained multiple co-crystal structures of PDE4 and bound inhibitors that show multiple regulatory domains closed across the active site of PDE4D and PDE4B. This structural insight, together with supporting mutagenesis and kinetic studies, suggests that steric hindrance to the active site is the mechanistic basis for PDE4 regulation in vivo and provides a paradigm for understanding the regulation of other PDE superfamily members. These structures also enabled the design of the first small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I_max ˜ 80–90%). These allosteric modulators have reduced potential to cause emesis while maintaining biological activity in cellular and in vivo models. These allosteric modulators are currently being explored for their ability to modulate cAMP levels in the CNS for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression.