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Bioorg Med Chem Lett. 2014 Sep 1;24(17):4141-50. doi: 10.1016/j.bmcl.2014.07.054. Epub 2014 Jul 25.

Structure-based optimization of non-peptidic Cathepsin D inhibitors.

Author information

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.

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

PMID:
25086681
DOI:
10.1016/j.bmcl.2014.07.054
[Indexed for MEDLINE]

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