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Heptares scientist report the first use of structure-based drug design to discover GPCR-targeted drug candidate

1st April 2013


Welwyn Garden City, UK, 25 January 2012 – Heptares Therapeutics, the leading GPCR drug discovery company, provides an update on recent scientific publications that highlight its unique ability to generate valuable information on GPCR structures and ligand binding. Such information has enabled Heptares to employ powerful structure-based drug design (SBDD) approaches to clinically important, yet historically intractable GPCR targets resulting in the discovery of novel drug leads.

In the first of two new papers published in Journal of Medicinal Chemistry, Heptares scientists describe how completely novel antagonists to the adenosine A2A receptor were identified using stabilised receptors (StaRs®) and a virtual screening approach. In silico screening of over half a million compounds resulted in 20 confirmed hits in vitro. These hits lack the undesirable furan and xanthine moieties common to many A2A antagonists. The binding modes of certain of these hits were refined using Heptares’ Biophysical Mapping™, allowing optimal interactions to be identified and potent antagonists designed that proved suitable for further optimisation.

The second J. Med. Chem. Paper  describes the structure-based optimisation of one of these series, which led to a preclinical candidate showing, by X-ray crystallography of receptor-ligand complexes, that these compounds bind in a novel mode deep in the orthosteric pocket. The authors describe how atom-efficient design results in leads with excellent pharmacokinetic and pharmacodynamic drug properties, and with best-in-class potential.  

Inhibition of the A2A receptor has been proved to be clinically effective in treating symptoms of Parkinson’s disease and may offer benefits in other CNS diseases. A candidate from the novel chemical series discussed is the subject of a partnership with Shire for further development in the area of neurological disorders. This is the first GPCR candidate to be discovered using a fully enabled SBDD process, from virtual screening through multi-parameter optimisation.

Further research presented by Heptares at the British Pharmacological Society meeting in December 2011  demonstrates Heptares’ capability to shed light on the pharmacology of existing small molecules that bind GPCRs and to enable the discovery of potentially first-in-class and best-in-class drug candidates with greater selectivity, potency and improved safety characteristics.

Using its unique GPCR platform, Heptares has assembled a rich pipeline of drug candidates targeting serious neurological (CNS) and metabolic disorders, including:

·       highly selective muscarinic M1 agonists with potential for improving cognition in schizophrenia and Alzheimer’s disease

·       novel allosteric modulators of mGlu2 (schizophrenia) and mGlu5 (anxiety/autism)

·       orexin antagonists targeting opportunities in chronic insomnia, anxiety and addiction

In addition, Heptares has signed commercial partnerships with leading pharma companies such as Takeda, AstraZeneca, MedImmune Shire and Novartis.

“Heptares continues to make rapid progress scientifically validating its powerful and unique approach to understanding and unlocking the potential of important clinically relevant GPCRs that previously have been inaccessible,” said Fiona Marshall, Heptares’ Chief Scientific Officer. “Structural information resulting from this approach provides Heptares with the ability to develop alternative discovery models to any used previously on GPCRs. This breakthrough science is now rapidly being applied by Heptares to create a pipeline of novel drug candidates across multiple therapeutic areas, and its power is increasingly being recognised by leading pharmaceutical companies.”




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