Structure–Activity relationship of benzo[b]thiophene-2-sulfonamide derivatives as novel human chymase inhibitors

Masaki, Hidekazu; Mizuno, Yusuke; Tatui, Akira; Murakami, Akira; Koide, Yoshinobu; Satoh, Shoji; Takahashi, Atsuo

doi:10.1016/j.bmcl.2003.08.040

Cited by 23 publications

(3 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The importance of hydrophobic features is confirmed for chymase inhibition [27], [30], [34]. Moreover, the presence of hydrogen bond acceptor features is also considered significant for inhibition of chymase enzyme [35]. In addition, the methodology to develop this hybrid pharmacophore model development is completely new and different from the common feature and structure-activity relationship based pharmacophore models employed in our previous studies for designing human chymase inhibitors [27].…”

Section: Resultsmentioning

confidence: 99%

Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

et al. 2013

View full text Add to dashboard Cite

Human chymase catalyzes the hydrolysis of peptide bonds. Three chymase inhibitors with very similar chemical structures but highly different inhibitory profiles towards the hydrolase function of chymase were selected with the aim of elucidating the origin of disparities in their biological activities. As a substrate (angiotensin-I) bound crystal structure is not available, molecular docking was performed to dock the substrate into the active site. Molecular dynamics simulations of chymase complexes with inhibitors and substrate were performed to calculate the binding orientation of inhibitors and substrate as well as to characterize conformational changes in the active site. The results elucidate details of the 3D chymase structure as well as the importance of K40 in hydrolase function. Binding mode analysis showed that substitution of a heavier Cl atom at the phenyl ring of most active inhibitor produced a great deal of variation in its orientation causing the phosphinate group to interact strongly with residue K40. Dynamics simulations revealed the conformational variation in region of V36-F41upon substrate and inhibitor binding induced a shift in the location of K40 thus changing its interactions with them. Chymase complexes with the most activecompound and substrate were used for development of a hybrid pharmacophore model which was applied in databases screening. Finally, hits which bound well at the active site, exhibited key interactions and favorable electronic properties were identified as possible inhibitors for chymase. This study not only elucidates inhibitory mechanism of chymase inhibitors but also provides key structural insights which will aid in the rational design of novel potent inhibitors of the enzyme. In general, the strategy applied in the current study could be a promising computational approach and may be generally applicable to drug design for other enzymes.

show abstract

Section: Resultsmentioning

confidence: 99%

Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

et al. 2013

View full text Add to dashboard Cite

show abstract

“…In 2003, Toa Eiyo patented [60] and published details of some benzo[ b ]thiophene-2-sulfonamide derivatives as novel human chymase inhibitors, one of which (TY-51076) ( Figure 5 ) inhibited recombinant human chymase with an IC 50 of 56 nM [61] .…”

Section: Toa Eiyo Ltdmentioning

confidence: 99%

Therapeutic potential of non-peptide chymase inhibitors

Doggrell¹

2008

Expert Opinion on Therapeutic Patents

View full text Add to dashboard Cite

“…Using a pharmacophore model describing the structural requirements of a chymase inhibitor associated to a database search, this group first identified a benzo[b]thiophene-2-sulfonamide compound, MWP00965, as a poor chymase inhibitor but stable in human plasma [99]. Subsequently, this lead compound was modified to produce TY-51076, a highly potent (IC 50 = 56 nM) and selective chymase inhibitor [100]. Unfortunately, in vivo data using TY-51076 were only presented in Japanese scientific meetings (Hidekazu Masaki, personal communication).…”

Section: Targeting Chymasementioning

confidence: 99%

Targeting Serine Proteases in Asthma

Guay¹,

Laviolette²,

Tremblay³

2006

CTMC

View full text Add to dashboard Cite

Leukocytes and lung structural cells contribute to the pathophysiology of asthma through the production of numerous mediators including serine proteases. Such proteases include mast cell tryptase and chymase; neutrophil elastase, cathepsin G and myeloblastin (proteinase 3); bronchial epithelial cell-derived transmembrane protease, serine 11D (human airway trypsin-like protease); cytotoxic T lymphocyte- and natural killer cell-derived granzyme B; and, eosinophil serine protease 1 (testisin). Considerable effort to develop potent and selective inhibitors, mostly non-peptidic, especially targeting tryptase and chymase have been made in the last few years. This review presents promising inhibitors, currently in the research and development pipeline. Some endogenous inhibitors and other compounds purified from non-human species are also discussed.

show abstract

Structure–Activity relationship of benzo[b]thiophene-2-sulfonamide derivatives as novel human chymase inhibitors

Cited by 23 publications

References 15 publications

Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

Molecular Modeling Study for Inhibition Mechanism of Human Chymase and Its Application in Inhibitor Design

Therapeutic potential of non-peptide chymase inhibitors

Targeting Serine Proteases in Asthma

Contact Info

Product

Resources

About