Discovery of Phosphodiesterase-4 Inhibitors: Serendipity and Rational Drug Design
Susanne C Feil, Jessica K Holien, Craig Morton, Nancy C Hancock, Philip E Thompson, Michael W Parker
Australian Journal of Chemistry | CSIRO PUBLISHING | Published : 2014
Phosphodiesterase 4 (PDE4), the primary cyclic AMP-hydrolysing enzyme in cells, is a promising drug target for a wide range of mental disorders including Alzheimer's and Huntington's diseases, schizophrenia, and depression, plus a range of inflammatory diseases including chronic obstructive pulmonary disease, asthma, and rheumatoid arthritis. However, targeting PDE4 is complicated by the fact that the enzyme is encoded by four very closely related genes, together with 20 distinct isoforms as a result of mRNA splicing, and inhibition of some of these isoforms leads to intolerable side effects in clinical trials. With almost identical active sites between the isoforms, X-ray crystallography ha..View full abstract
The authors thank Pat Ho, Jack Martin, Jacob Nankervis, Diana Neale, and Hooi Ling Ng for their contributions to the PDE4 drug discovery work described here. This work was supported by a National Health and Medical Research Council of Australia (NHMRC) Development Grant to Jack Martin and Matthew Gillespie, and M.W.P. Infrastructure support from the NHMRC Independent Research Institutes Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Support Program to St. Vincent's Institute are gratefully acknowledged. J.K.H. is a joint Cure Cancer/Leukemia Foundation Postdoctoral Fellow. M.W.P. is an NHMRC Fellow.