Novel Benzo[1,4]diazepin-2-one Derivatives as Endothelin Receptor Antagonists

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• 作者：Martin H. Bolli ; Judith Marfurt ; Corinna Grisostomi ; Christoph Boss ; Christoph Binkert ; Patrick Hess ; Alexander Treiber ; Eric Thorin ; Keith Morrison ; Stephan Buchmann ; Daniel Bur ; Henri Ramuz ; Martine
• 刊名：Journal of Medicinal Chemistry
• 出版年：2004
• 出版时间：May 20, 2004
• 年：2004
• 卷：47
• 期：11
• 页码：2776 - 2795
• 全文大小：571K
• 年卷期：v.47,no.11(May 20, 2004)
• ISSN：1520-4804

文摘

Since its discovery in 1988 by Yanagisawa et al., endothelin (ET), a potent vasoconstrictor,has been widely implicated in the pathophysiology of cardiovascular, cerebrovascular, and renaldiseases. Many research groups have embarked on the discovery and development of ET receptorantagonists for the treatment of such diseases. While several compounds, e.g., ambrisentan 2,are in late clinical trials for various indications, one compound (bosentan, Tracleer) is beingmarketed to treat pulmonary arterial hypertension. Inspired by the structure of ambrisentan2, we designed a novel class of ET receptor antagonists based on a 1,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-2-one scaffold. Here, we report on the preparation as well as the in vitroand in vivo structure-activity relationships of these derivatives. Potent dual ET_A/ET_B receptorantagonists with affinities in the low nanomolar range have been identified. In addition, severalcompounds efficiently reduced arterial blood pressure after oral administration to Dahl saltsensitive rats. In this animal model, the efficacy of the benzo[e][1,4]diazepin-2-one derivativerac-39au was superior to that of racemic ambrisentan, rac-2.