Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors

Bekkali, Younes; Thomson, D. S.; Betageri, Raj; Emmanuel, Michel J.; Hao, Ming‐Hong; Hickey, Eugene R.; Liu, Weimin; Patel, Usha; Ward, Yancey D.; Young, Erick R.R.; Nelson, Richard M.; Kukulka, Alison; Brown, Marie; Crane, Kathleen; White, Della; Freeman, Dorothy M.; Labadia, Mark E.; Wildeson, Jessi; Spero, Denice M.

doi:10.1016/j.bmcl.2007.02.046

Cited by 12 publications

(4 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many of the recent CatS inhibitors contain an electrophilic motif (e.g., a nitrile), which binds covalently and reversibly to cysteine C25 (vide infra) in the active site, forming a thioimidate . This binding motif has been employed, for example, in the aminocyclopropane nitrile A by Merck Frosst or in the succinamide derivative B and more recent triazoles both described by Boehringer Ingelheim. Cyclohexyl-substituted derivatives (e.g., C ) were developed as CatK inhibitors at Roche more than a decade ago and served as a basis for the development of selective CatS inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds

et al. 2013

View full text Add to dashboard Cite

Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Its side chain is able to perform a conformational switch leading to a remarkable plasticity of the S2 pocket of cathepsin S. − Therefore, besides the side chains of aliphatic amino acids preferred in P2 position of cathepsin S substrates, , several hydrophobic moieties of inhibitors can be accommodated in the S2 pocket. Examples include fluorinated phenyl or alkylphenyl, , cyclohexyl, and 4-methylcyclohexyl groups and the residues of phenylalanine, , (naphthalen-2-yl)alanine, leucine, , cyclohexylalanine , methyl-branched cycloalkylalanines, (1,2,3,4-tetrahydronaphthalen-2-yl)alanine, and S -(isobutyl)cysteine sulfone . The last amino acid was a particular suitable building block to achieve strong cathepsin S inhibition and selectivity over cathepsins L, K, and B …”

Section: Resultsmentioning

confidence: 99%

Selective Nitrile Inhibitors To Modulate the Proteolytic Synergism of Cathepsins S and F

et al. 2012

View full text Add to dashboard Cite

A series of dipeptide nitriles with different P3 substituents was designed to explore the S3 binding pocket of cathepsin S. Racemic 7-16 and the enantiopure derivative (R)-22 proved to be potent inhibitors of human cathepsin S and exhibited notable selectivity over human cathepsins L, K, and B. Inhibition of cathepsin F, the functional synergist of cathepsin S, was not observed. The azadipeptide analogue of 22, compound 26, was highly potent but nonselective.

show abstract

“…Other cysteine proteases, Cat K and L, play a significant role in numerous important physiological and pathological processes, such as bone resorption, cancer progression, and atherosclerosis [1,8,9,10]. Different trials were done for discovery of novel selective Cat S inhibitors, which should be safer therapeutic agents than nonselective inhibitors by avoiding off-target side effects [11,12,13,14,15,16]. Cathepsin K (Cat K) is a cysteine protease that is highly expressed by osteoclasts and has been shown to be a key enzyme involved in bone resorption [17] secreted in the extracellular acidic lacunae at the interface of the osteoclast and bone tissue, the enzyme’s primarily role consists of type I collagen degradation, one of the main constituents of bone matrix.…”

Section: Introductionmentioning

confidence: 99%

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits

et al. 2016

View full text Add to dashboard Cite

Abstract:The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. However, there is still a shortage of efficient and accurate computational methods with powerful capability to study and hence predict compound selectivity properties. In this work, we propose an affordable machine learning method to perform compound selectivity classification and prediction. For this purpose, we have collected compounds with reported activity and built a selectivity database formed of 153 cathepsin K and S inhibitors that are considered of medicinal interest. This database has three compound sets, two K/S and S/K selective ones and one non-selective KS one. We have subjected this database to the selectivity classification tool 'Emergent Self-Organizing Maps' for exploring its capability to differentiate selective cathepsin inhibitors for one target over the other. The method exhibited good clustering performance for selective ligands with high accuracy (up to 100 %). Among the possibilites, BAPs and MACCS molecular structural fingerprints were used for such a classification. The results exhibited the ability of the method for structure-selectivity relationship interpretation and selectivity markers were identified for the design of further novel inhibitors with high activity and target selectivity.

show abstract

Identification of a novel class of succinyl-nitrile-based Cathepsin S inhibitors

Cited by 12 publications

References 15 publications

Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds

Identification of Potent and Selective Cathepsin S Inhibitors Containing Different Central Cyclic Scaffolds

Selective Nitrile Inhibitors To Modulate the Proteolytic Synergism of Cathepsins S and F

Self Organizing Map-Based Classification of Cathepsin k and S Inhibitors with Different Selectivity Profiles Using Different Structural Molecular Fingerprints: Design and Application for Discovery of Novel Hits

Contact Info

Product

Resources

About