title: Novel β-amino acid derivatives as inhibitors of cathepsin A.
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 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.
authors.affiliation: Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, 65926 Frankfurt, Germany. sven.ruf@sanofi.com
authors.forename: Sven
authors.initials: S
authors.lastname: Ruf
authors.forename: Christian
authors.initials: C
authors.lastname: Buning
authors.forename: Herman
authors.initials: H
authors.lastname: Schreuder
authors.forename: Georg
authors.initials: G
authors.lastname: Horstick
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Linz
authors.forename: Thomas
authors.initials: T
authors.lastname: Olpp
authors.forename: Josef
authors.initials: J
authors.lastname: Pernerstorfer
authors.forename: Katrin
authors.initials: K
authors.lastname: Hiss
authors.forename: Katja
authors.initials: K
authors.lastname: Kroll
authors.forename: Aimo
authors.initials: A
authors.lastname: Kannt
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.forename: Dominik
authors.initials: D
authors.lastname: Linz
authors.forename: Thomas
authors.initials: T
authors.lastname: Hübschle
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.forename: Klaus
authors.initials: K
authors.lastname: Wirth
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Thorsten
authors.initials: T
authors.lastname: Sadowski
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D043402:Cathepsin A / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D011480:Protease Inhibitors; D043402:Cathepsin A