Novel 尾-Amino Acid Derivatives as Inhibitors of Cathepsin A

详细信息    查看全文

• 作者：Sven Ruf ; Christian Buning ; Herman Schreuder ; Georg Horstick ; Wolfgang Linz ; Thomas Olpp ; Josef Pernerstorfer ; Katrin Hiss ; Katja Kroll ; Aimo Kannt ; Markus Kohlmann ; Dominik Linz ; Thomas H眉bschle ; Hartmut R眉tten ; Klaus Wirth ; Thorsten Schmidt ; Thorsten Sadowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：55
• 期：17
• 页码：7636-7649
• 全文大小：637K
• 年卷期：v.55,no.17(September 13, 2012)
• ISSN：1520-4804

文摘

Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel 尾-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials.