title: Structure-based optimization of non-peptidic Cathepsin D inhibitors.
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.
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany. Electronic address: ulrich.graedler@merckgroup.com.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Grädler
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Christos
authors.initials: C
authors.lastname: Tsaklakidis
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Klein
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Werkmann
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Lindemann
authors.affiliation: Proteros Biostructures GmbH, Bunsenstrasse 7a, 82152 Martinsried, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Maskos
authors.affiliation: Merck KGaA, Merck Serono Research, Small Molecule Platform, Frankfurter Str. 250, 64293 Darmstadt, Germany.
authors.forename: Birgitta
authors.initials: B
authors.lastname: Leuthner
mesh_terms: D002402:Cathepsin D / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; C533922:CTSD protein, human; D002402:Cathepsin D
keywords: Cathepsin D; Non-peptidic inhibitor; Structure-based design; X-ray structure