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Advances in ion channel drug discovery

The Potassium channel Enterprise library Posted on: 20 May 03


A highly targeted library is available for the screening of potassium channel blockers or potassium channel openers

Advances in ion channel drug discovery: The Potassium channel Enterprise library

Ion channels play an important role in numerous cell types and occur as large families of related genes with cell-specific expression patterns. In the post-genomic era, progress in transcription profiling revealing the tissue specific distributions of ion channels and a greater understanding of these proteins will mean that channels will play an increasingly important role as therapeutic drug targets in the future. These advances combined with improved cell-based assays will make ion channels a favorable class of selective, tissue specific, drug targets. Currently, there are active pharmaceutical research and development programs involving ion channels in a number of areas, including asthma, inflammation, arrhythmia and CNS disorders (see our recent feature "Ion Channels as Therapeutic Targets for Multiple Diseases").

Drugs targeting ion channels already generate over $6 billion in sales per annum. According to the FDA, the number of new approved drugs targeting ion channels is equal to or even higher than that for drugs targeting proteases, polymerases and reverse transcriptases. But, despite their remarkable physiological value, ion channels have remained a relatively unexploited therapeutic target class, especially in comparison to target areas such as G-protein coupled receptors or kinases. Major challenges have been the lack of high throughput screening (HTS) assays and the availability of targeted libraries of candidate ion channel modulators.

ChemOvation is a leading provider of medicinal chemistry services to both pharmaceuticals and biotechnology sector. Over the past 3 years ChemOvation has used it's expertise in offering tailored integrated drug discovery programs to accelerate channel-based drug discovery. In particular ChemOvation has focused on potassium channels.

Potassium channels play critical roles in a wide variety of physiological processes, including the regulation of heart rate, muscle contraction, neurotransmitter release, neuronal excitability, insulin secretion, epithelial electrolyte transport, cell volume regulation, immune function and cell proliferation. As such, potassium channels have been recognized as potential therapeutic drug targets for many years. Today, more than 80 potassium channel and potassium channel-related genes have been identified, and an understanding of the molecular composition and the function of many important native potassium currents is becoming clearer. This field represents a major growth area and in the past few months alone LeadDiscovery has focused on the emergence of, for example, the Kv1.3 channel as an exciting target for immunotherapeutics and the Kv1.5 channel as a target for the unmet condition, pulmonary hypertension. Equally the K(ATP) channel remains of key interest to cardiovascular diseases.

Unfortunately, as with channels in general, potassium channel target selection and the identification of selective potassium channel modulators has remained problematic. LeadDiscovery and ChemOvation have pooled their resources to overcome these problems. LeadDiscovery's CustomReport service has now been made available to help companies conceptualize the selection of potassium channels for drug discovery programs [more]. On the other hand, using a combination of in-house computational expertise, organic chemistry and medicinal chemistry knowledge, ChemOvation has now designed a high value potassium channel targeted library called the "Potassium Channel Enterprise Library". This library is unique to ChemOvation and is available on a non-exclusive, easy access basis.

Although the "Potassium Channel Enterprise Library" is highly targeted towards potassium channels, it has also been developed with diversity across the various potassium channels in mind. The "Potassium Channel Enterprise Library" is therefore well suited for screening against a wide range of potassium channels increasing the likelihood of identifying hits for novel channels.

This library can be screened in house or assayed through ChemOvation's kinase screening services and discovery programs. ChemOvation provides a full drug discovery service including re-supply of hits, tailored hit validation/expansion series and a highly efficient hit-to-lead optimisation program based on an integrated drug discovery platform. It is envisaged that hit-to-lead optimisation will include the development of further libraries based around the hits identified.

Design Parameters used to generate the Ion Channel Enterprise Library: Using proprietary informatics tools, ChemOvation's medicinal chemists have designed and validated routes to a number of unique templates based around known kinase pharmacophores.

Molecular modelling has heavily influenced the design of the "Potassium Channel Enterprise Library". By conducting diversity analysis of all monomers, the library probes a wide spectrum of available chemical space. By also including modelling filters such as pharmacokinetic and physio-chemical parameters you can be sure the "Potassium Channel Enterprise Library" offers an excellent "Lead Finding" opportunity against a range of therapeutically important kinase targets.

Each template can be further elaborated into focused libraries should there be a need to exploit any leads that may arise. Due to ChemOvation's no-compromise approach to monomer selection based on SAR, these libraries provide significant lead finding potential over typical "biased" or "diverse" compound collections.

Library synthesis utilises parallel synthetic technologies and state-of-the-art mass directed semi-automated purification.

[further details]


Last updated on: 27/08/2010 11:40:18

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