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Novel β-amino acid derivatives as inhibitors of cathepsin A.

Ruf S, Buning C, Schreuder H, Horstick G, Linz W, Olpp T, Pernerstorfer J, Hiss K, Kroll K, Kannt A, Kohlmann M, Linz D, Hübschle T, Rütten H, Wirth K, Schmidt T, Sadowski T
J Med Chem 55 7636-49 (2012)
Cited: 14 times
EuropePMC logo PMID: 22861813

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.

Articles - 4az0 mentioned but not cited (2)

  1. Proteolytic activation of human cathepsin A. Kolli N, Garman SC. J Biol Chem 289 11592-11600 (2014)
  2. An In Silico Target Fishing Approach to Identify Novel Ochratoxin A Hydrolyzing Enzyme. Dellafiora L, Gonaus C, Streit B, Galaverna G, Moll WD, Vogtentanz G, Schatzmayr G, Dall'Asta C, Prasad S. Toxins (Basel) 12 E258 (2020)


Articles citing this publication (12)

  1. Cathepsin A mediates susceptibility to atrial tachyarrhythmia and impairment of atrial emptying function in Zucker diabetic fatty rats. Linz D, Hohl M, Dhein S, Ruf S, Reil JC, Kabiri M, Wohlfart P, Verheule S, Böhm M, Sadowski T, Schotten U. Cardiovasc Res 110 371-380 (2016)
  2. Cathepsin A inhibition attenuates myocardial infarction-induced heart failure on the functional and proteomic levels. Petrera A, Gassenhuber J, Ruf S, Gunasekaran D, Esser J, Shahinian JH, Hübschle T, Rütten H, Sadowski T, Schilling O. J Transl Med 14 153 (2016)
  3. Development and characterization of small bispecific albumin-binding domains with high affinity for ErbB3. Nilvebrant J, Astrand M, Löfblom J, Hober S. Cell Mol Life Sci 70 3973-3985 (2013)
  4. Serine carboxypeptidase SCPEP1 and Cathepsin A play complementary roles in regulation of vasoconstriction via inactivation of endothelin-1. Pan X, Grigoryeva L, Seyrantepe V, Peng J, Kollmann K, Tremblay J, Lavoie JL, Hinek A, Lübke T, Pshezhetsky AV. PLoS Genet 10 e1004146 (2014)
  5. Cardiac drug-drug interaction between HCV-NS5B pronucleotide inhibitors and amiodarone is determined by their specific diastereochemistry. Lagrutta A, Regan CP, Zeng H, Imredy JP, Koeplinger K, Morissette P, Liu L, Wollenberg G, Brynczka C, Lebrón J, DeGeorge J, Sannajust F. Sci Rep 7 44820 (2017)
  6. Tolerability, safety, and pharmacokinetics of the novel cathepsin A inhibitor SAR164653 in healthy subjects. Tillner J, Lehmann A, Paehler T, Lukacs Z, Ruf S, Sadowski T, Pinquier JL, Ruetten H. Clin Pharmacol Drug Dev 5 57-68 (2016)
  7. Cathepsin A Mediates Ventricular Remote Remodeling and Atrial Cardiomyopathy in Rats With Ventricular Ischemia/Reperfusion. Hohl M, Erb K, Lang L, Ruf S, Hübschle T, Dhein S, Linz W, Elliott AD, Sanders P, Zamyatkin O, Böhm M, Schotten U, Sadowski T, Linz D. JACC Basic Transl Sci 4 332-344 (2019)
  8. Crystal structure of cathepsin A, a novel target for the treatment of cardiovascular diseases. Schreuder HA, Liesum A, Kroll K, Böhnisch B, Buning C, Ruf S, Sadowski T. Biochem Biophys Res Commun 445 451-456 (2014)
  9. Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice. Hohl M, Mayr M, Lang L, Nickel AG, Barallobre-Barreiro J, Yin X, Speer T, Selejan SR, Goettsch C, Erb K, Fecher-Trost C, Reil JC, Linz B, Ruf S, Hübschle T, Maack C, Böhm M, Sadowski T, Linz D. J Biol Chem 295 12605-12617 (2020)
  10. In Silico Structural Analysis of Serine Carboxypeptidase Nf314, a Potential Drug Target in Naegleria fowleri Infections. Madero-Ayala PA, Mares-Alejandre RE, Ramos-Ibarra MA. Int J Mol Sci 23 12203 (2022)
  11. Editorial Cathepsin A Inhibitors to Treat Heart Disease: Much Potential, Many Questions. Cowling RT. JACC Basic Transl Sci 4 345-347 (2019)
  12. Characterization of a new nitrilase from Hoeflea phototrophica DFL-43 for a two-step one-pot synthesis of (S)-β-amino acids. Zhang ZJ, Cai RF, Xu JH. Appl Microbiol Biotechnol 102 6047-6056 (2018)


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