Pernerstorfer J

References (1)

Title : Novel beta-amino acid derivatives as inhibitors of cathepsin A. - Ruf_2012_J.Med.Chem_55_7636
Author(s) : Ruf S , Buning C , Schreuder H , Horstick G , Linz W , Olpp T , Pernerstorfer J , Hiss K , Kroll K , Kannt A , Kohlmann M , Linz D , Hubschle T , Rutten H , Wirth K , Schmidt T , Sadowski T
Ref : Journal of Medicinal Chemistry , 55 :7636 , 2012
Abstract : 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 beta-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.
ESTHER : Ruf_2012_J.Med.Chem_55_7636
PubMedSearch : Ruf_2012_J.Med.Chem_55_7636
PubMedID: 22861813
Gene_locus related to this paper: human-CTSA