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Nonpeptide inhibitors of cathepsin G: optimization of a novel beta-ketophosphonic acid lead by structure-based drug design. There is a pressing need to develop new treatments for chronic obstructive pulmonary disease (COPD), as no currently available drug therapy reduces the relentless progression of the diseases, chronic obstructive bronchitis and emphysema, falling under the umbrella of COPD. World-wide, 600 million people suffer from COPD, with some three million dying from the disease each year representing a globally market of US$2.8 billion US. There is a particular need to develop drugs that control the underlying inflammatory and destructive processes that cause COPD. There have been few therapeutic advances in the drug therapy of COPD. Those targets that are in development for COPD have been discussed in our recent and hugely popular DiscoveryDossier, produced in collaboration with Prof Peter Barnes "Therapeutic and pharmaceutical approaches to COPD" (Click here for access). One group of targets that received our attention was the cathepsin family. Cathepsins K, S and L are macrophage-derived elastolytic cysteine proteases that are released from macrophages. These cathepsins as well as cathepsin G have all been therapeutic targets for the treatment of COPD as well as a number of other inflammatory diseases. To date the development of cathepsin, especially cathepsin G, inhibitors has been largely unsuccessful. This situation appears to be changing as indicated by a recent report emerging from Johnson & Johnson. By employing high-throughput screening, researchers identified beta-ketophosphonic acid as a moderate inhibitor of Cathepsin G. Subsequent to successful crystallography, this group was able to optimize this lead. Modeling the 3-position of the 2-naphthyl ring of beta-ketophosphonic acid, which occupies the S1 pocket of cathepsin G, an analogue was identified which displayed nanomolar potency. From these results, it is evident that the beta-ketophosphonic acid unit can form the basis of a novel class of serine protease inhibitors and further studies to determine the therapeutic potential of this series are eagerly awaited Link to journal abstract:
Adapted from Greco et al, J Am Chem Soc 2002 Apr 17;124(15):3810-1 Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk LeadDiscovery and BioPortfolio aims to provide reliable, insightful analysis on the biotechnology industry. However, this information is provided "as is" and no representations or warranties either express or implied of completeness, accuracy, or of any other nature are made with respect to this information. This information is neither an offer to sell nor a solicitation to buy the securities of any company. This information contains forward-looking statements, which involve risks and uncertainties which may not be listed. The biotechnology industry is an emerging industry and the securities of the companies mentioned in this report have a very high degree of risk and volatility. For this reason, this information is supplied on the condition that the reader will make his or her own determination as to its suitability for any purpose prior to any use of this information. The employees and officers of LeadDiscovery and BioPortfolio may hold positions in some or all of the stocks discussed in this report. This abstract has been produced by LeadDiscovery Ltd. Founded by life scientists for life scientists we aim to help industry identify cutting edge drug discovery options and academic/biotech institutions maximize the potential of their research. Abstracts strictly reflect the opinion of LeadDiscovery's editorial panel. While all reasonable efforts are made to ensure the accuracy of information provided LeadDiscovery and the publisher BioPortfolio, takes no responsibility for incorrect or misleading information. LeadDiscovery is designed for educational and drug development purposes only and is not intended or designed to offer medical advice or advice of any sort, and must not be used for such purpose. The information provided through LeadDiscovery and BioPortfolio should not be used for diagnosing or treating a health problem or a disease and no reliance should be placed on any information contained in this abstract or elsewhere on LeadDiscovery's and BioPortfolio's website. It is not intended to be a substitute for professional care. If you have or suspect you may have a health problem, you should consult your physician or other health care provider. |
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