Linked Life Data

16033281

Source:http://linkedlifedata.com/resource/pubmed/id/16033281

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pubmed-article:16033281pubmed:abstractTextEfforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.lld:pubmed
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pubmed-article:16033281pubmed:articleTitleDiscovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.lld:pubmed
pubmed-article:16033281pubmed:affiliationDepartment of Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, USA. lawrence.hamann@bms.comlld:pubmed
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