AN-2728,Phosphodiesterase PDE4 inhibitor.pdf

CONTENTS Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .607 Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .607 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .607 Preclinical pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .609 Pharmacokinetics and metabolism . . . . . . . . . . . . . . . . . . . . . . . . .610 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .610 Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .611 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .612 Organization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .612 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612 SUMMARY Psoriasis and atopic dermatitis are non-contagious inflammatory skin diseases with a chronic and relapsing course. Currently, although sev- eral treatments are available to control these disorders, other therapies are under investigation. The available therapies help relieve the symp- toms and increase the time between flare-ups. However, due to the chronic course of these diseases, becoming refractory to long-term treat- ment is often a possibility. AN-2728 is an investigational drug targeting the inflammatory pathway. It is a novel boron-containing molecule that inhibits the release of proinflammatory cytokines by binding to the ac- tive water in the bimetal center of the active site of the phosphodiesterase PDE4 enzyme. AN-2728 has shown a promising safety profile and is generally well tolerated following topical application in patients with mild to moderate psoriasis and atopic dermatitis. In several phase II studies, the primary endp