Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors

Ishihara, Tsukasa; Seki, Norio; Hirayama, Fukushi; Orita, Masaya; Koshio, Hiroyuki; Taniuchi, Yuta; Sakai-Moritani, Yumiko; Iwatsuki, Yoshiyuki; Kaku, Seiji; Kawasaki, Tomihisa; Matsumoto, Yuzo; Tsukamoto, Shin‐ichi

doi:10.1016/j.bmc.2007.03.066

Cited by 11 publications

(2 citation statements)

References 41 publications

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“…The SAR trend of MMS R3 paralleled that of MMS R7 [37] (entry 7 in Table 4.a), although two scaffolds in this pair differed significantly from each other (scaffold similarity = 0.35, MMS similarity = 0.67). Other relationships between MMS pairs R2-R8 [38] (entry 8 in Table 4.a), R3-R9 [38] (entry 9 in Table 4.a), R2-R10 [34] (entry 10 in Table 4.a), and R2-R11 [39] (entry 11 in Table 4.a) were detected with MMS similarities = 0.67, 0.56, 0.35, and 0.28, respectively.…”

Section: Detection Of Similar Mms Using a Direct Searchmentioning

confidence: 96%

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

Ishihara

Mori

Munakata

et al. 2017

CBIJ

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Here we report a new drug design workflow that facilitates the transfer of structure-activity relationships (SARs) and recommends alternative fragments from SAR databases. We first prepare two collections of matched molecular series (MMS) comprising a query set of compounds with their SARs and a set derived from reference SAR databases. The second step detects MMS from the reference SAR sources, which identifies profiles similar to a query MMS according to integrated similarities of scaffold shapes and SAR trends. The third step enumerates new compounds with improved activity profiles compared with a query compound computed using a collaborative filtering algorithm. Our workflow detected direct and latent relationships between a query MMS and those derived from the reference SAR sources. Retrospective application of this workflow to the identification of factor Xa inhibitors yielded recommendations with higher predictive accuracy than a conventional quantitative SAR technique. Moreover, potent S1 binding elements were identified using SAR knowledge independent of information about ligand-protein complexes.Key Words: in silico drug design, de novo drug design, data mining, matched molecular pair Area of Interest:In silico drug discovery

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Section: Detection Of Similar Mms Using a Direct Searchmentioning

confidence: 96%

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

Ishihara

Mori

Munakata

et al. 2017

CBIJ

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“…The in vitro selectivity towards thrombin and the crystal structures of these compounds were investigated, and it was proved that compound 29 had a remarkable selectivity (>10 3 ×) and inhibition for thrombin, whereas even the concentration was reached to 200 μM, it had no inhibitory effect on other enzymes such as urokinase, FXa, plasmin, chymotrypsin and trypsin. Based on the strategy of combining amidine derivatives and their prodrugs, Ishihara et al [50] synthesized a series of N-benzenesulfonylpiperidine derivatives to excavate potent and orally active FXa inhibitors (Fig. 26).…”

Section: Other Derivativesmentioning

confidence: 99%

Progress of thrombus formation and research on the structure-activity relationship for antithrombotic drugs

Guo

Qian

et al. 2022

European Journal of Medicinal Chemistry

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Lewis Acid‐Catalyzed Ring‐Opening Functionalizations of 1,4‐Epoxy‐1,4‐dihydronaphthalenes

et al. 2013

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Since 1,4-epoxy-1,4-dihydronaphthalenes are smoothly converted to 1-naphthol derivatives via unstable cation intermediates formed by the acid-catalyzed ring-opening reaction of the 1,4-epoxy moiety of 1,4-epoxy-1,4-dihydronaphthalenes, their nucleophilic functionalization using the cation intermediates as an active species is extremely difficult. We have accomplished the Lewis acid-catalyzed carboncarbon and carbon-nitrogen bond formations associated with the ring-opening of 1,4-epoxy-1,4-dihydronaphthalenes using nucleophiles such as allyltrimethylsilanes, trimethylsilyl cyanide and trimetylsilyl azide, by using the stabilization effect of the cation intermediate based on the introduction of appropriate substituents into the bridgehead positions of 1,4epoxy-1,4-dihydronaphthalenes to give the corresponding unique and multifunctionalized naphthalene derivatives. The present reactions could provide excellent regioselective functionalization methods using unsymmetrical substrates, which are quite difficult to achieve using transition metal-induced procedures. 521 Lewis Acid-Catalyzed Ring-Opening Functionalizations of 1,4-Epoxy-1,4-dihydronaphthalenes Scheme 5. Ring-opening functionalizations using nitrogenbridged substrate (11).Scheme 4. Proposed reaction mechanism.

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Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors

Cited by 11 publications

References 41 publications

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

A Novel Fragment Recommendation Workflow using Direct and Indirect Transfer of SAR According to Integrated Similarities of Scaffold Motifs and SAR Trends: Application to Identifying Factor Xa Inhibitors

Progress of thrombus formation and research on the structure-activity relationship for antithrombotic drugs

Lewis Acid‐Catalyzed Ring‐Opening Functionalizations of 1,4‐Epoxy‐1,4‐dihydronaphthalenes

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