Merck & Co develop new leads for the treatment of bipolar disorder through the development of a new HTS assay of inositol monophosphatase inhibitors
SummaryDailyUpdates 31st March: Bipolar disorder affects over 2 million people in the US alone. Lithium, which inhibits inositol monophosphatase, has long been a first line mood stabilizer used in the treatment of this condition. Merck & Co have now developed a new cell-based HTS assay to identify novel inositol monophosphatase inhibitors which will hopefully lead to improved treatments of bipolar disorder.
DailyUpdates 31st March: Bipolar disorder affects over 2 million people in the US alone. Lithium, which inhibits inositol monophosphatase, has long been a first line mood stabilizer used in the treatment of this condition. Merck & Co have now developed a new cell-based HTS assay to identify novel inositol monophosphatase inhibitors which will hopefully lead to improved treatments of bipolar disorder.
Technological advancements in high-throughput screening (HTS) in combination with the development of technologies able to create large chemistry libraries are fuelling the development of numerous novel products.
The market for novel high-throughput screening products is estimated to reach $225M in 2004 and growth will continue at an annual rate of 19% to reach approximately $540M worldwide in 2009 (for an analysis of the HTS market click here). Paralleling this expansion is an increase in the development of novel HTS assays within the drug development sector. In the April edition of the Journal of Biomolecular Screening, researchers from Merck & Co report on the development of an HTS cell-based screening using scintillation proximity assay for the discovery of inositol phosphatase inhibitors. This new assay is anticipated to lead to the development of novel treatments of bipolar disorder.
The bipolar disorder market is experiencing a renewed expansion in product life-cycle management. This disorder, which affects over 2 million people in the US alone, is characterized by cycling between depressive and manic or hypomanic states. Presently, mood stabilizers are the basis of treatment, although the antipsychotics led by Zyprexa, are evolving as a new therapeutic strategy (for an analysis of Zyprexa click here). The most commonly used mood stabilizers are valproate (divalproex) and lithium with the latter acting through the depletion of inositol.
The mechanism of action of lithium involves at least in part the inhibition of inositol monophosphatase, which leads to depletion of brain cells of myo-inositol and consequently to dampening of phosphoinositide signalling.
Enzyme-based assays have been traditionally used in compound screening to identify inositol monophosphatase inhibitors. A cell-based screening assay in which the compound needs to cross the cell membrane before reaching the target enzyme offers a new approach for discovering novel structure leads of the inositol monophosphatase inhibitor.
Merck & Co have developed a cell-based scintillation proximity assay to allow the determination of inositol monophosphatase activity. This improvement which allows the measurement of enzyme activity in its native form and physiological environment is hoped to allow the identification of improved leads. To validate this assay a large compound collection was assayed under HTS conditions and several novel inositol monophosphatase inhibitors were identified.
(source DailyUpdates 31st March; for a full abstract of the original papers see J Biomol Screen. 2004 Apr;9(2):132-40; for further information on bipolar disorder see either Bipolar Disorders - Zyprexa Sets the Mood for Revenue Growth or Antipsychotics - Novel Antipsychotics Driving Market Evolution - for information on HTS technology go to Novel High-Throughput Screening)In this edition of DailyUpdates, LeadDiscovery also highlights the design, synthesis, and SAR of anthranilamide-based factor Xa inhibitors...the efficacy of BAL5788 in a mouse model of acute pneumococcal pneumonia...a resource for large-scale RNA-interference-based screens in mammals...and much more.