Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors

Nagahara, Takayasu; Yokoyama, Yukio; Inamura, K.; Katakura, S.; Komoriya, Satoshi; Yamaguchi, Hitoshi; Hara, Tsuyoshi; Iwamoto, Masahiro

doi:10.1021/jm00034a018

Cited by 182 publications

(80 citation statements)

References 11 publications

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“…The structure of the DX-9065a-bound factor Xa was the first inhibitor complex structure published (13). DX-9065a was developed by Daiichi Pharmaceutical Co., Ltd., Tokyo, and inhibits factor Xa with K i ϭ 41 nM; IC 50 ϭ 92 nM at pH 8.4 (46,47) and K i ϭ 103 nM; IC 50 ϭ 208 nM at pH 7.4 (data not shown). Although the chemical structure and the binding mode of this inhibitor are different from those of FX-2212a (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for chemical inhibition of human blood coagulation factor Xa

Kamata

Kawamoto

Honma

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

133

111

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Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery for thromboembolic diseases. An inhibitor has been synthesized and the crystal structure of the complex between Des[1-44] factor Xa and the inhibitor has been determined by crystallographic methods in two different crystal forms to 2.3-and 2.4-Å resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a) was found to bind to the active site of factor Xa in both crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes hydrophobic interactions with the factor Xa aryl-binding site. Several water molecules meditate inhibitor binding to residues in the active site. In contrast to the earlier crystal structures of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44] factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal growth factor-like domains of factor Xa are well ordered in both our crystal forms as well as the region between the two domains, which recently was found to be the binding site of the effector cell protease receptor-1. This structure provides a basis for designing next generation inhibitors of factor Xa.Thromboembolic disease is caused by the improper functioning of the blood coagulation process. Blood clots are formed by a zymogen activation cascade of serine proteases, and the last protease of the cascade, thrombin, converts fibrinogen to fibrin, which cross-links to form blood clots (for a review, see ref.

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Section: Discussionmentioning

confidence: 99%

Structural basis for chemical inhibition of human blood coagulation factor Xa

Kamata

Kawamoto

Honma

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

133

111

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“…Edoxaban was first synthesized in Japan in 1994 in the Daiichi laboratories, 13 and the preclinical work was also done in Japan. 14 After the first-in-human, proof of concept, and dose-ranging work was completed, again much of it in Japan, 15 there were 3 observations that suggested edoxaban was worthy of further investigation: there were very few food and drug interactions; it was available in pill form that provided a stable level of an-Clinical Research and Therapeutics on a chip" is placed in a microfluid test chamber, which is then sealed and drugs can be infused as well as electrical currents delivered to stimulate the cells.…”

Section: Review Antman Emmentioning

confidence: 99%

Clinical Research and the Development of Medical Therapeutics

Antman

2014

Circ J

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Clinical research plays a central role in the development of medical therapeutics, but the current system is estimated to take 10-15 years from initial discovery to regulatory approval, at a cost of approximately US$1 billion. Contrast the paths by which 2 anticoagulant options for atrial fibrillation were discovered and ultimately established as treatment options in clinical medicine. Warfarin was discovered by serendipity and compared with placebo in relatively small trials; this was associated with a low cost of development. The new oral anticoagulants were synthesized to provide highly specific, targeted inhibition of critical steps in the coagulation system. They were compared with warfarin for prevention of stroke and systemic embolic events in large, phase 3 trials; this resulted in very expensive development programs. Neither of these paths is desirable for future development of therapeutics. We need to focus on innovative approaches at the preclinical level (systems approach, greater use of inducible pluripotent stem cells, use of novel bioengineering platforms) and clinical trial level (adaptive design, greater use of new and emerging technology). Focusing on disruptive innovations for development of medical therapeutics has the potential to bring us closer to the goal of precision medicine where safer, more effective treatments are discovered in a more efficient system. (Circ J 2014; 78: 1267 -1271

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“…DX-9065a, which is the progenitor of small-molecule fXa inhibitors, was found to possess an amidine moiety that binds the S1 pocket [1], and numerous structurally similar amidine derivatives were investigated as well [2]. Other studies of fXa inhibitors revealed that anthranilamide derivatives with a 4-methoxyphenyl group occupy the S1 binding pocket of fXa [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

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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Dibasic (Amidinoaryl)propanoic Acid Derivatives as Novel Blood Coagulation Factor Xa Inhibitors

Cited by 182 publications

References 11 publications

Structural basis for chemical inhibition of human blood coagulation factor Xa

Structural basis for chemical inhibition of human blood coagulation factor Xa

Clinical Research and the Development of Medical Therapeutics

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

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