Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 1780 - 1785 |
| Number of pages | 6 |
| Journal | Australian Journal of Chemistry |
| Volume | 67 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2014 |
Cite this
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Discovery of phosphodiesterase-4 inhibitors: Serendipity and rational drug design. / Feil, Susanne C; Holien, Jessica K; Morton, Craig James; Hancock, Nancy C; Thompson, Philip; Parker, Michael William.
In: Australian Journal of Chemistry, Vol. 67, No. 12, 2014, p. 1780 - 1785.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Discovery of phosphodiesterase-4 inhibitors: Serendipity and rational drug design
AU - Feil, Susanne C
AU - Holien, Jessica K
AU - Morton, Craig James
AU - Hancock, Nancy C
AU - Thompson, Philip
AU - Parker, Michael William
PY - 2014
Y1 - 2014
N2 - 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 has played a critical role in the discovery and development of safer PDE4 inhibitors. Here we describe our discovery of a novel class of highly potent PDE4 via a virtuous cycle of structure-based drug design and serendipity.
AB - 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 has played a critical role in the discovery and development of safer PDE4 inhibitors. Here we describe our discovery of a novel class of highly potent PDE4 via a virtuous cycle of structure-based drug design and serendipity.
UR - http://www.publish.csiro.au/?act=view_file&file_id=CH14397.pdf
U2 - 10.1071/CH14397
DO - 10.1071/CH14397
M3 - Article
VL - 67
SP - 1780
EP - 1785
JO - Australian Journal of Chemistry
JF - Australian Journal of Chemistry
SN - 0004-9425
IS - 12
ER -