PlumX Metrics
Embed PlumX Metrics

Novel β-amino acid derivatives as inhibitors of cathepsin A

Journal of Medicinal Chemistry, ISSN: 0022-2623, Vol: 55, Issue: 17, Page: 7636-7649
2012
  • 42
    Citations
  • 0
    Usage
  • 45
    Captures
  • 0
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

Article Description

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 β-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. © 2012 American Chemical Society.

Bibliographic Details

Ruf, Sven; Buning, Christian; Schreuder, Herman; Horstick, Georg; Linz, Wolfgang; Olpp, Thomas; Pernerstorfer, Josef; Hiss, Katrin; Kroll, Katja; Kannt, Aimo; Kohlmann, Markus; Linz, Dominik; Hübschle, Thomas; Rütten, Hartmut; Wirth, Klaus; Schmidt, Thorsten; Sadowski, Thorsten

American Chemical Society (ACS)

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

Provide Feedback

Have ideas for a new metric? Would you like to see something else here?Let us know