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The emergence of vasopressin receptor antagonists The antidiuretic hormone vasopressin is a cyclic nonapeptide involved in the control of body fluid osmolality, blood volume, blood pressure, and vascular tone. It acts by binding to G protein-coupled membrane receptors. Three subtypes have been identified to date. The vasopressin V1A receptor mediates cell contraction and proliferation, platelet aggregation, release of coagulation factor, and glycogenolysis. V1B on the other hand is expressed in the anterior pituitary and mediates the release of ACTH, beta-endorphin, and prolactin. Finally, the V2 receptor is exclusively expressed in the kidney, and defects in this receptor result in nephrogenic diabetes insipidus. The involvement of vasopressin in several pathological states has been reported recently and the selective blockade of the different vasopressin receptors may therefore confer therapeutic benefit in a number of different diseases. Sanofi-Synthelabo researchers have recently published data describing a chemical series of 1-phenylsulfonylindolines with vasopressin receptor binding properties. The lead of this series, SR49059, a V1a receptor antagonist prototype displays high affinity for animal and human V1a receptors and antagonized various V1a AVP-induced effects in vitro and in vivo including, platelet aggregation, vascular smooth muscle cell proliferation, hypertension and coronary vasospasm. Structural modification of SR49059 has yielded highly specific V2 receptor antagonists (N-arylsulfonyl-oxindoles), amongst them SR121463 which possesses powerful oral aquaretic properties in various animal species and in man. SR121463 is well-tolerated and dose-dependently increases urine output without affecting electrolyte balance in contrast to classical diuretics. SR121463 demonstrates therapeutic efficacy in models of cirrhosis and ocular hypertension. This molecule is currently in phase II development for the treatment of heart failure. Finally, further chemical developments in the oxindole family have led to the first specific and orally active V1b receptor antagonists including the lead, SSR149415 which is being developed as an anxiolytic and anti-depressant. The increased availability of specific vasopressin receptor antagonists is expected to lead to the rapid growth of this field. December, 2002
Adapted from Serradeil-Le Gal et al, Prog Brain Res 2002;139:197-210 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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