2. Academic Validation
  3. Structure-based optimization of non-peptidic Cathepsin D inhibitors

Structure-based optimization of non-peptidic Cathepsin D inhibitors

  • Bioorg Med Chem Lett. 2014 Sep 1;24(17):4141-50. doi: 10.1016/j.bmcl.2014.07.054.
Ulrich Grädler 1,  Paul Czodrowski 2,  Christos Tsaklakidis 2,  Markus Klein 2,  Daniela Werkmann 2,  Sven Lindemann 2,  Klaus Maskos 3,  Birgitta Leuthner 2
Affiliations

Affiliations

  • 1 Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany. Electronic address: ulrich.graedler@merckgroup.com.
  • 2 Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
  • 3 Proteros Biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany.
PMID: 25086681 DOI: 10.1016/j.bmcl.2014.07.054
Abstract

We discovered a novel series of non-peptidic acylguanidine inhibitors of Cathepsin D as target for osteoarthritis. The initial HTS-hits were optimized by structure-based design using CatD X-ray structures resulting in single digit nanomolar potency in the biochemical CatD assay. However, the most potent analogues showed only micromolar activities in an ex vivo glycosaminoglycan (GAG) release assay in bovine cartilage together with low cellular permeability and suboptimal microsomal stability. This new scaffold can serve as a starting point for further optimization towards in vivo efficacy.

Keywords

Cathepsin D; Non-peptidic inhibitor; Structure-based design; X-ray structure.

Figures
Products