New Anticoagulant Drugs

Weitz, Jeffrey I.; Hirsh, Jack

doi:10.1378/chest.119.1_suppl.95s

Cited by 157 publications

(79 citation statements)

References 136 publications

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“…In this manuscript, pharmacologic prophylaxis is discussed with each clinical setting. A summary of the major classes of pharmacologic agents used in VTE prophylaxis along with their mechanism of action and dosing [9][10][11][12][13] are presented in Table 1.…”

Section: Methods Of Thromboprophylaxismentioning

confidence: 99%

Prophylaxis for Venous Thrombo-Embolism in Neurocritical Care: A Critical Appraisal

2009

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Venous thrombo-embolism (VTE) is frequently encountered in critically ill neurological and neurosurgical patients admitted to intensive care units. This patient population includes those with brain neoplasm, intracranial hemorrhage, ischemic stroke, subarachnoid hemorrhage, pre- and post-operative patients undergoing neurosurgical procedures and those with traumatic brain injury, and acute spinal cord injury (SCI). There is a wide variability in clinical practice for thromboprophylaxis in these patients, in part due to paucity of data based on randomized clinical trials. Here, we review the current literature on the incidence of VTE in the critically ill neurological and neurosurgical patients as well as appraise available data to support particular practice paradigms for specific subsets of these patients. Data synthesis was conducted via search of Medline, Cochrane databases, and manual review of article bibliographies. Critically ill neurological and neurosurgical patients have higher susceptibility to VTE. Intermittent compression devices with or without anti-thrombotics is generally the method of choice for thromboprophylaxis. Low molecular weight heparin is the method of choice in certain patient subgroups such as those with SCI and ischemic stroke. Inferior vena cava filters may play a role in thromboprophylaxis in selected cases. Without clear guidelines that can be universally applied to this diverse group of patients, prophylaxis for VTE should be tailored to the individual patient with cautious assessment of benefits versus risks. There is a need for higher level evidence to guide VTE prophylaxis in certain subgroups of this patient population.

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Section: Methods Of Thromboprophylaxismentioning

confidence: 99%

Prophylaxis for Venous Thrombo-Embolism in Neurocritical Care: A Critical Appraisal

2009

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“…[8][9][10][11] In previous papers, 1,2) we reported the synthesis and biological activity of new compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, and through this investigation M55113 (1) (IC 50 : 0.06 mM) and M55551 (2) (IC 50 : 0.006 mM) were confirmed to be somewhat favorable as FXa inhibitors.In order to investigate the role played a piperazine moiety in these compounds, we focused on comparison of the activity of compounds which have an ethylenediamine structure in place of the piperazine ring of M55113 and M55551. The present paper concerns the synthesis of such compounds together with their inhibition of FXa.…”

mentioning

confidence: 66%

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors III. Effect of Ring Opening of Piperazinone Moiety on Inhibition

Nishida

Miyazaki

Mukaihira

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Recently, direct inhibition of factor Xa (FXa), which links the intrinsic and extrinsic mechanisms in the blood coagulation cascade, [3][4][5][6][7] has emerged as an attractive strategy for the discovery of novel antithrombotic agents. [8][9][10][11] In previous papers, 1,2) we reported the synthesis and biological activity of new compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, and through this investigation M55113 (1) (IC 50 : 0.06 mM) and M55551 (2) (IC 50 : 0.006 mM) were confirmed to be somewhat favorable as FXa inhibitors.In order to investigate the role played a piperazine moiety in these compounds, we focused on comparison of the activity of compounds which have an ethylenediamine structure in place of the piperazine ring of M55113 and M55551. The present paper concerns the synthesis of such compounds together with their inhibition of FXa. ChemistrySynthesis of ethylenediamine derivative 9 corresponding to M55113 and M55551 was achieved as shown in Chart 1. Compound 6, prepared by the reaction of N-tert-butoxycarbonyl-1,2-diaminoethane hydrochloride (4) with 6-chloro-2-naphthalenesulfonyl chloride (5) under basic conditions, was deprotected with trifluoroacetic acid (TFA) to yield compound 7. The condensation of 7 with 1-(4-pyridinyl)-4-piperidinecarboxaldehyde (8) prepared by Swern oxidation 12) of the corresponding methanol yielded the desired ethylenediamine derivative 9 in the presence of reducing agent. 13) The route of synthesis of compound 13, which contains an amide group on the ethylenediamine moiety of compound 9, is shown in Chart 2. Compound 11, prepared by the reaction Discovery Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412-8524, Japan. Received November 5, 2003; accepted February 2, 2004 Compounds containing an ethylenediamine structure in place of the piperazine ring of M55113 (1) and M55551 (2) were synthesized to investigate the effects of a piperazine moiety and evaluated for activity as factor Xa (FXa) inhibitors. Most such compounds, however, exhibited lower activity (1/10-1/100) than that of M55113 and M55551 as FXa inhibitors.

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“…[7][8][9][10][11] Comparison of hirudin [12][13][14][15][16] (a thrombin inhibitor) and tick anticoagulant peptide [17][18][19][20][21][22] (a FXa inhibitor) suggests that inhibition of FXa may result in less risk of bleeding, leading to a more favorable safety/efficacy ratio. [23][24][25][26][27] Direct inhibition of FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [28][29][30][31][32][33][34] Fondaparinux (Arixtra ® ), [35][36][37] which was approved as the first selective FXa inhibitor in 2002, has been proven to be clinically useful.…”

mentioning

confidence: 99%

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors VI. A Series of New Derivatives Containing N,S- and N,SO2-Spiro Acetal Scaffolds

Saitoh

Nishida

Mukaihira

et al. 2007

CHEMICAL & PHARMACEUTICAL BULLETIN

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In the course of development of factor Xa (FXa) inhibitors, we have found unique compounds containing an N,O-and an N,N-spiro acetal structure. It appeared that the difference in overall conformation due to the N,Xspiro acetal structure might be important for FXa inhibitory activity. Therefore, other N,X-spiro acetal structures, an N,S-and an N,SO 2 -spiro acetal, were developed as analogues of the N,X-spiro acetal structure. Compound 7b (N,S-spiro acetal structure) was found to have the strongest activity in these series of N,X-spiro acetal compounds, which had ever been synthesized. 4,5)

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New Anticoagulant Drugs

Cited by 157 publications

References 136 publications

Prophylaxis for Venous Thrombo-Embolism in Neurocritical Care: A Critical Appraisal

Prophylaxis for Venous Thrombo-Embolism in Neurocritical Care: A Critical Appraisal

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors III. Effect of Ring Opening of Piperazinone Moiety on Inhibition

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors VI. A Series of New Derivatives Containing N,S- and N,SO2-Spiro Acetal Scaffolds

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