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Re-discovering PDE3 inhibitors - New opportunities for a long neglected target

Thompson, Philip E.; Manganiello, Vincent and Degerman, Eva LU (2007) In Current Topics in Medicinal Chemistry 7(4). p.421-436
Abstract
The PDE3 enzymes or "low Kin cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a... (More)
The PDE3 enzymes or "low Kin cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then took at past clinical evaluation of PDE3 inhibitors that occurred without that. information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Current Topics in Medicinal Chemistry
volume
7
issue
4
pages
421 - 436
publisher
Bentham Science Publishers
external identifiers
  • wos:000244703100010
  • scopus:33847672708
ISSN
1873-4294
DOI
10.2174/156802607779941224
language
English
LU publication?
yes
id
c9617d4a-51d8-4376-a9d4-34b35370c703 (old id 671708)
date added to LUP
2007-12-21 14:33:15
date last changed
2017-10-01 03:55:55
@article{c9617d4a-51d8-4376-a9d4-34b35370c703,
  abstract     = {The PDE3 enzymes or "low Kin cGMP-inhibited phosphodiesterases" have long been established as important mediators of cellular physiology, and synthetic PDE3 inhibitors have been critical to the delineation of the enzymes' roles. Yet despite decades of progress on the biology of these enzymes, the medicinal chemistry landscape relating to PDE3 inhibitors has remained essentially unchanged since the mid 1990's. Up until then the field was at the cutting edge of drug design; without the tools of molecular and structural biology, molecules of high potency were being achieved using logical pharmacophore models and lead modification. Yet virtually all the impetus went out of this area on the back of failures at the clinic and PDE3 as a therapeutic target largely fell out of favour. A decade later and with the "new" technologies of structural and molecular biology breathing new life into PDE3 research in general, PDE3 inhibitors are sought for target validation in an array of therapeutic applications. In this review, we examine the current state of PDE3 research; firstly we summarize the structural and functional properties of PDE3 enzymes with particular attention to the heterogeneity within this class of enzymes which differ markedly in expression, localisation and means of regulation across various tissue types. It is the structural and functional complexity of the PDE3 enzymes that underpins the re-emergence of PDE3s roles as targets for drug design. We then took at past clinical evaluation of PDE3 inhibitors that occurred without that. information and which may have had a significant bearing on the outcome of those drug discovery efforts. Finally we look at current approaches to the design of PDE3 inhibitors which utilize that historic data but also incorporate new inputs from structural biology and combinatorial chemistry.},
  author       = {Thompson, Philip E. and Manganiello, Vincent and Degerman, Eva},
  issn         = {1873-4294},
  language     = {eng},
  number       = {4},
  pages        = {421--436},
  publisher    = {Bentham Science Publishers},
  series       = {Current Topics in Medicinal Chemistry},
  title        = {Re-discovering PDE3 inhibitors - New opportunities for a long neglected target},
  url          = {http://dx.doi.org/10.2174/156802607779941224},
  volume       = {7},
  year         = {2007},
}