The Discovery of YM-60828: A Potent, Selective and Orally-Bioavailable Factor Xa Inhibitor

Hirayama, Fukushi; Koshio, Hiroyuki; Katayama, Naoko; Kurihara, Hiroyuki; Taniuchi, Yuta; Sato, Kazuo; Hisamichi, Nami; Sakai-Moritani, Yumiko; Kawasaki, Tomihisa; Matsumoto, Yuzo; Yanagisawa, Isao

doi:10.1016/s0968-0896(01)00418-7

Cited by 40 publications

(25 citation statements)

References 32 publications

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“…115 Modification of the amidine at P4, removal of the chiral center, and replacement of the central carboxylic acid with an sulfamoylacetic acid, as in 22, yielded the more potent 23 (YM-60828; fXa IC 50 5 2.3 nM, fIIa IC 50 4100,000 nM, EC 2 Â PT 5 700 nM) and 24 (fXa IC 50 5 3.8 nM, fIIa IC 50 4100,000 nM, EC 2 Â PT 5 940 nM). 116 Further SAR exploration of the sulfamoylacetic acid scaffold led to a series of interesting analogues, which are exemplified by 25À27 (Fig. 15).…”

Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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Thromboembolic diseases are the leading causes of morbidity and mortality in the developed world. Anticoagulants provide effective treatment for venous or arterial thromboembolism. Two coagulation factors, factor Xa (fXa) and thrombin, are the primary targets under active investigation for anticoagulant therapy. fXa, in contrast to the multifunctional roles of thrombin in the coagulation cascade, converts prothrombin to thrombin collectively at the junction of the intrinsic and extrinsic pathway of coagulation. The effectiveness of fXa inhibitors as antithrombotic agents and their potentially reduced bleeding risks may offer superior therapeutic profiles with respect to thrombin inhibitors. After decades of research, many fXa inhibitors are now in the advanced stages of clinical trials. Unlike most reviews, which only provide incremental updates, this review provides an overview of fXa and the medicinal chemistry of its inhibitors. Overviews on coagulation models, antithrombotic therapy, and fXa will be provided, followed by the evolution of the medicinal chemistry of fXa inhibitors over the past few decades.

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Section: Synthetic Direct Fxa Inhibitorsmentioning

confidence: 99%

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Lee¹,

Player²

2011

Medicinal Research Reviews

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“…However, we examined the mutagenic potential of these cinnamyl derivatives and found that all the derivatives exhibited positive results in Ames tests. 24) On the other hand, the reported naphthylamidine derivative YM-75466 25) (Fig. 2) exhibited a negative result in the test.…”

Section: Resultsmentioning

confidence: 92%

Discovery of R-142086 as a Factor Xa (FXa) Inhibitor: Syntheses and Structure-Activity Relationships of Cinnamyl Derivatives

Noguchi

Tanaka

Nishimata

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Warfarin is widely used as a sole oral anticoagulant for the treatment and prevention of thromboembolic diseases. However, many reports have mentioned the defects of warfarin. It requires periodic monitoring because of its narrow therapeutic window and, in addition, warfarin interacts with many different foods and drugs. [4][5][6] Therefore, new anticoagulants based on novel mechanisms need to be developed. Recently, blood coagulation factor Xa (FXa) has attracted considerable attention as a novel anticoagulation target.FXa acts at the convergence point of the intrinsic pathway and the extrinsic pathway in a blood coagulation cascade. 7)FXa converts prothrombin into thrombin and leads to fibrin clot formation. It is thought that the inhibition of FXa effectively diminishes the thrombin generation and, as a result, leads to the inhibition of clot formation. Indeed, many FXa inhibitors have been synthesized and their anticoagulant activities reported. 8,9) In these reports, FXa inhibitors exhibit less bleeding risk than warfarin and thrombin inhibitors. We have also conducted research to discover orally-active novel FXa inhibitors. [10][11][12][13] Previously, we found that the series of cinnamyl derivatives represented by 1 and 2 produced potent in vitro FXa inhibitory activities and high selectivity. Moreover, these compounds also exhibited potent ex vivo anticoagulant activities in hamsters after oral administration.However, regarding the chemical structure, these compounds are highly hydrophilic with two amidino groups. It seems that enhancement of these compounds' lipophilicity may improve the plasma concentration after oral administration and the resulting oral anticoagulant activity. Similarly, conversion of these compounds into their prodrug forms may be promising for high oral activity. Herein, we describe our synthetic efforts and further evaluations to discover R-142086 with ex vivo anticoagulant activity in dogs.Chemistry Cinnamyl derivatives with various imidoyl group on the piperidine ring were synthesized as shown in Chart 1. Piperidine 3 13) was reacted with iminoethers 14,15) under basic conditions, followed by acid hydrolysis to give corresponding bisamidine derivatives 4a-g. Other cinnamyl derivatives with a five-membered cyclic imidoyl group (6a, 6b) were synthesized by the same methods as compound 4d. Monoamidine derivatives were synthesized as shown in Chart 2. A t-butoxycarbonyl (Boc) group of compound 7 13) was converted to a methyl group (8a) by treatment with formaldehyde solution and formic acid. Compound 7 was also deprotected under an acidic condition to give piperidine 9. This compound was then subjected to a usual condition to give acetamide 8b. Piperidine 9 was converted to corresponding N-alkyl or N-aryl compounds (8c-k) by reductive amination with aldehydes or ketones (method A), or treatment with alkyl-or arylbromide under a basic condition (method B), or Pd-catalyzed amination with arylbromide and phosphine 10 (method C).16) Reduction of the nitro group of compounds 8a-k afforde...

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“…Entry A is a collection of YM466 derivatives [19]. Entry B is a set of analogous naphtoanilide derivatives [20], and entry C contains relative 1,4-diazepan derivatives [21].…”

Section: Detection Of Similar Mms Using a Direct Searchmentioning

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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The Discovery of YM-60828: A Potent, Selective and Orally-Bioavailable Factor Xa Inhibitor

Cited by 40 publications

References 32 publications

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Developments in factor Xa inhibitors for the treatment of thromboembolic disorders

Discovery of R-142086 as a Factor Xa (FXa) Inhibitor: Syntheses and Structure-Activity Relationships of Cinnamyl Derivatives

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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