Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate

Aoyama, Hiroshi; Ijuin, Ryosuke; Kato, Jun‐ya; Urushiyama, Sarasa; Tetsuhashi, Masashi; Hashimoto, Yuichi; Yokomatsu, Tsutomu

doi:10.1016/j.bmcl.2015.06.039

Cited by 3 publications

(2 citation statements)

References 18 publications

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“…Finally, starting from 2-N-Boc-aminopyridine-5-boronic acid 66 and the phthalimide Michael acceptor 62, we prepared the thrombin inhibitor 67 in 51% yield. 38 These results highlight the application of our methodology to prepare three medicinally significant compounds (Scheme 1).…”

Section: Scheme 1 Drug Synthesis Amentioning

confidence: 67%

“…By employing the commercially available boronic acid 64 and N -Boc-3-pyrrolin-2-one 61 , we synthesized the FDA-approved phosphodiesterase-4 (PDE4) inhibitor rolipram 65 in 43% yield. Finally, starting from 2- N -Boc-aminopyridine-5-boronic acid 66 and the phthalimide Michael acceptor 62 , we prepared the thrombin inhibitor 67 in 51% yield . These results highlight the application of our methodology to prepare three medicinally significant compounds (Scheme ).…”

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confidence: 99%

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General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

2020

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Carbon-centered radicals are indispensable building blocks for modern synthetic chemistry. In recent years, visible light photoredox catalysis has become a promising avenue to access C-centered radicals from a broad array of latent functional groups, including boronic acids. Herein, we present an aqueous protocol wherein water features a starring role to help transform aliphatic, aromatic, and heteroaromatic boronic acids to C-centered radicals with a bioinspired flavin photocatalyst. These radicals are used to deliver a diverse pool of alkylated products, including three pharmaceutically relevant compounds, via open-shell conjugate addition to disparate Michael acceptors. The mechanism of the reaction is investigated by computational studies, deuterium labeling, radical-trapping experiments, and spectroscopic analysis.

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confidence: 67%

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confidence: 99%

General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

2020

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Development of Biologically Active Compounds on the Basis of Phosphonic and Phosphinic Acid Functionalities

Yokomatsu

2017

YAKUGAKU ZASSHI

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Phosphonic and phosphinic acids, especially a-heteroatom-substituted ones, possess unique structural and physical features which enable them to act as hydrotically stable analogs to biological phosphates in biological processes. They also act as mimetics in the transition state of the protease-induced hydrolysis of dipeptides. Theˆrst half of this review focuses on selected new synthetic methods developed by our research group for the stereoselective synthesis of aheteroatom-substituted phosphonic and phosphinic acid derivatives, including modiˆed nucleotide analogs and phosphinyl dipeptide isosteres. In the latter half, this review summarizes the utility of di‰uoromethylenephosphonic acids and phosphonic acid esters in the development of enzyme inhibitors against protein tyrosine phosphatases, sphingomyelinases, purine nucleoside phosphorylases and thrombin. The enzyme inhibitors developed were used as probes to elucidate signal transductions and the mechanisms of enzyme actions. Theˆndings of the studies are brie‰y described.

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The Research Progress of Direct Thrombin Inhibitors

Sun

Yang

Zhang

et al. 2020

MRMC

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: Blood coagulation is the process of changing the blood from the flowing state to the gel state. It is an important part of the hemostatic function. Coagulation is a process by which a series of coagulation factors are sequentially activated, and finally thrombin is formed to form fibrin clot. Direct thrombin inhibitors are important anticoagulant drug. These drugs can selectively bind to the active site of thrombin, inhibit thrombin activity, have strong action and high specificity, and have important significance in the clinical treatment of thrombus diseases. Some of them come from natural products of animals or plants, and many of them have been applied in clinic. The other part is derived from the design, synthesis and activity studies of small molecule inhibitors. This review discusses the progress of direct thrombin inhibitors in recent years.

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Discovery of non-competitive thrombin inhibitor derived from competitive tryptase inhibitor skeleton: Shift in molecular recognition resulted from skeletal conversion of carboxylate into phosphonate

Cited by 3 publications

References 18 publications

General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

General Access to C-Centered Radicals: Combining a Bioinspired Photocatalyst with Boronic Acids in Aqueous Media

Development of Biologically Active Compounds on the Basis of Phosphonic and Phosphinic Acid Functionalities

The Research Progress of Direct Thrombin Inhibitors

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