Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors

Ueno, Hiroshi; Yokota, Kazumichi; Hoshi, Jun‐ichi; Yasue, Katsutaka; Hayashi, Mikio; Uchida, Isamu; Aisaka, Kazuo; Hase, Yastinori; Katoh, Susumu; Cho, Hidetsura

doi:10.1016/j.bmcl.2004.10.033

Cited by 8 publications

(6 citation statements)

References 14 publications

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“…Human thrombin, an enzyme of about 300 residues, is interesting both as a drug target related to blood coagulation and as a representative serine protease. Binding and structural data are available for a wide variety of ligands ( [8,141,168,177] and others), and have already been used as the basis for free energy simulations [17,186,187]. Some of the experimental binding data, obtained calorimetrically, highlight interesting trends, such as non-additivity (positive coupling) between substitutions at different locations on the chemical scaffolds of two compound series [8].…”

Section: Thrombinmentioning

confidence: 99%

Predicting binding free energies: Frontiers and benchmarks

Mobley

Gilson

2016

Preprint

134

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Binding free energy calculations based on molecular simulations provide predicted affinities for biomolecular complexes. These calculations begin with a detailed description of a system, including its chemical composition and the interactions between its components. Simulations of the system are then used to compute thermodynamic information, such as binding affinities. Because of their promise for guiding molecular design, these calculations have recently begun to see widespread applications in early stage drug discovery. However, many challenges remain to make them a robust and reliable tool. Here, we highlight key challenges facing these calculations, describe known examples of these challenges, and call for the designation of standard community benchmark test systems that will help the research community generate and evaluate progress. In our view, progress will require careful assessment and evaluation of new methods, force fields, and modeling innovations on well-characterized benchmark systems, and we lay out our vision for how this can be achieved.

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Section: Thrombinmentioning

confidence: 99%

Predicting binding free energies: Frontiers and benchmarks

Mobley

Gilson

2016

Preprint

134

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“…The release of fondaparin sodium, which is a synthetic pentasaccharide, proved the clinical effectiveness of FXa inhibitors as anticoagulants . This situation prompted us to disclose our experimental results on novel FXa inhibitors . As reported previously, we obtained a potent FXa inhibitor 4 , which is a benzimidazole derivative with the side chain oriented to the prime site of FXa (see Figure ) 4a…”

Section: Introductionmentioning

confidence: 68%

“…This situation prompted us to disclose our experimental results on novel FXa inhibitors . As reported previously, we obtained a potent FXa inhibitor 4 , which is a benzimidazole derivative with the side chain oriented to the prime site of FXa (see Figure ) 4a 1 Chemical structures of key compounds 1 − 5 . …”

Section: Introductionmentioning

confidence: 77%

“…This compound showed moderate FXa inhibitory activity (IC 50 = 3.34 ± 0.25 μM),1a demonstrating that it had sufficient potential for further studies on structure−activity relationships. Introduction of basic substituents on the nitrogen atom of the piperidine ring provided compounds 7 − 13 (Table ). 4b,c Among the compounds with a pyridinyl group, quinolinyl group, pyridinylmethyl group, or aminobenzyl group, compound 8 (with a pyridin-4-yl group) showed more potent FXa inhibitory activity (IC 50 = 0.056 ± 0.003 μM). This potent activity of compound 8 might be explained by interaction of the protonated pyridine ring with the S4 site, which favors a positive charge, and by formation of a hydrogen bond between the protonated nitrogen atom of pyridine and Glu 97, as expected from the docking simulation of compounds with FXa.…”

Section: Resultsmentioning

confidence: 99%

“…We focused on two basic parts, the S1 and S4 sites, and designed a fundamental skeleton (compound 5 ) as follows. First, we selected an N -amidinotetrahydroisoquinoline ring that was expected to completely fill the S1 pocket of FXa and to interact with Asp 189 4b. Then a 4-piperidinylmethyloxy group was selected for position 7 of the tetrahydroisoquinoline ring as a spacer for the introduction of basic substituents because the nitrogen atom of the piperidinyl group could be oriented toward the S4 site…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure−Activity Relationships of Novel Selective Factor Xa Inhibitors with a Tetrahydroisoquinoline Ring

et al. 2005

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A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.

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Tetrahydroisoquinolines

2018

Privileged Structures in Drug Discovery

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Discovery of novel tetrahydroisoquinoline derivatives as potent and selective factor Xa inhibitors

Cited by 8 publications

References 14 publications

Predicting binding free energies: Frontiers and benchmarks

Predicting binding free energies: Frontiers and benchmarks

Synthesis and Structure−Activity Relationships of Novel Selective Factor Xa Inhibitors with a Tetrahydroisoquinoline Ring

Tetrahydroisoquinolines

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