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BMS-191095, a K(ATP) channel opener with improved cardioprotective properties More than one million new and recurrent cases of coronary attack occurred in the US in 1998. Forty percent of these patients died, 220,000 before even reaching hospital, making coronary heart disease the single leading cause of death in America. Heart disease most commonly results from atherosclerosis and associated risk factors including obesity and hyperlipidemia. Treatment is thus designed to slow the development of atherosclerosis, usually through the use of anti-thrombotic and/or anti-coagulant therapies, or in the event of coronary attack to reverse ischemia, limit infarct size, reduce cardiac work and to prevent recurrence. Immediate treatment of myocardial infarction includes the use of thrombolytics to reverse ischemia (see "Heart/Cardiovascular disease 2002" for an analysis of pharmaceutical opportunities in this area). The term preconditioning refers to the paradoxical phenomenon that pretreatment with a potential noxious stress-stimulus can increase cellular tolerance to subsequent noxious stress-stimuli. This was first described in an experimental model in dogs in which short-lasting periods of myocardial ischemia resulted in reduced infarction during a subsequent long-lasting coronary artery occlusion. Efforts to identify therapeutic candidates that induce preconditioning have dramatically increased over recent years. Such treatments may be of use in high-risk patients with stable coronary artery and during elective surgical procedures. ATP-sensitive potassium (K(ATP)) channels are inhibited by intracellular ATP and thus couple the metabolic state of the cell to its electrical activity. K(ATP) channels are found in both the mitochondria and in the sarcolemma. Opening the mitochondrial K(ATP) channels by molecules such as nicorandil leads to preconditioning of the myocardium and reduces infarct size, however the use of this therapy may be limited by systemic vasodilatation (which can compromise diseased myocardium) and changes in cardiac electrophysiology, effects that are associated with the sarcolemma K(ATP) channel. In contrast to nicorandil, BMS-191095 is a selective mitochondrial K(ATP) opener that protects against myocardial ischemia without altering peripheral or coronary hemodynamic status or cardiac electrophysiology. This molecule has therefore been advanced as a cardioprotective agent with a reduced risk of side-effects compared to first generation K(ATP) openers. Further development of this molecule and other similar representative from this pharmacological class should result in the development of improved treatments for patients with cardiovascular disease December, 2002
Adapted from Grover & Atwal, Cardiovasc Drug Rev 2002 Summer;20(2):121-36 Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk Projects such as these are overviewed in full DiscoveryDossiers. 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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