Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P1) region

Lo, Ho Yin; Nemoto, Peter A.; Kim, Jin Man; Hao, Ming‐Hong; Qian, Kevin; Farrow, Neil A.; Albaugh, Daniel; Fowler, Danielle M.; Schneiderman, Richard D.; August, Elias; Martin, Leigh R.; Hill-Drzewi, Melissa; Pullen, Steven S.; Takahashi, Hidenori; Lombaert, Stéphane De

doi:10.1016/j.bmcl.2011.05.126

Cited by 17 publications

(7 citation statements)

References 20 publications

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“…A literature-to-lead pharmacophore based campaign was initiated around inhibitor TPC-806 (Figure ), and benzimidazolone analogue 1 was rapidly identified as a potent proprietary scaffold with comparable chymase potency (<100 nM) and selectivity (∼14-fold) over cathepsin G. The benzimidazolone and benzimidazole analogues shared common SAR with respect to the S1 binding substituent as well as the carboxylate side chain . While potency similar to the literature inhibitors was achieved, liabilities observed for the benzimidazoles also tracked.…”

Section: Introductionmentioning

confidence: 94%

“…The mixture was stirred for 1 h at room temperature and then acidified to pH 2 with 1 N HCl. The resulting precipitate was collected and purified using reverse phase HPLC to afford 13 as a white solid ( 3-[3-(6-Chloro-2-oxo-2,3-dihydro-1H-indol-4-ylmethyl)-2oxo-2,3-dihydrobenzoimidazol-1-yl]hexanoic Acid (14). Alcohol 25 (700 mg, 2.4 mmol), triphenylphosphine (716 mg, 2.7 mmol), 3-(2-oxo-2,3-dihydrobenzoimidazol-1-yl)hexanoic acid ethyl ester 35 (755 mg, 2.7 mmol), and THF (16 mL) were combined and cooled to 0 °C in an ice−water bath.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…15 To further optimize the benzimidazolones, a costructure of compound 1 was determined with chymase (PDB code 3S0N). 14 The general pharmacophore for this noncovalent, noncatalytic interacting structural class consists of a lipophilic P1 motif that is bridged to an acidic moiety though a 5−6 aromatic system. The directionality of the P1 side chain is mediated by substitution patterns around the 5−6 aromatic core, and the interactions between the prototypical P1 motifs with the protein at the time were thought to be primarily driven through van der Waals interactions.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

Taylor

Padyana²,

Abeywardane³

et al. 2013

J. Med. Chem.

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Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from.

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Section: Introductionmentioning

confidence: 94%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

Taylor

Padyana²,

Abeywardane³

et al. 2013

J. Med. Chem.

Self Cite

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“…In this study, four different 3D structures of chymase bound with its inhibitors such as 3N7O, 1T31, 3SON, and 2HVX were selected as input for structure-based pharmacophore generation [9], [32], [33], [34]. The generated four pharmacophore models along with their excluded volume spheres and geometrical constrain are illustrated in Figure 4.…”

Section: Resultsmentioning

confidence: 99%

A Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors

et al. 2013

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Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure–based pharmacophore models. One ligand–based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well.

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“…After structural and functional similarity analysis, the resulting list of putative off‐targets was further filtered via more computationally intensive protein–ligand docking. A set of four compounds reported as chymase inhibitors with their diverse experimentally known inhibitory activity (IC 50 ) data was compiled from the literature . This set includes TPC‐806 which is the first reported noncovalent chymase inhibitor and has been in phase II clinical trials for heart failure since 2007 .…”

Section: Methodsmentioning

confidence: 99%

Finding off‐targets, biological pathways, and target diseases for chymase inhibitors via structure‐based systems biology approach

et al. 2015

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Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. Here, we develop a robust computational strategy that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Putative off-targets for chymase inhibitors were identified through various structural and functional similarity analyses along with molecular docking studies. Finally, literature survey was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Tissue kallikreins, granzyme M, neutrophil elastase, and mesotrypsin are also identified as off-targets. These off-targets and their associated pathways are elucidated for the effects of inflammation, cancer, hemorrhage, thrombosis, and central nervous system diseases (Alzheimer's disease). Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors.

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Benzimidazolone as potent chymase inhibitor: Modulation of reactive metabolite formation in the hydrophobic (P1) region

Cited by 17 publications

References 20 publications

Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies

A Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors

Finding off‐targets, biological pathways, and target diseases for chymase inhibitors via structure‐based systems biology approach

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