Structure-Based Design of Novel Guanidine/Benzamidine Mimics:  Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants

Lam, Patrick Y.S.; Clark, C. G.; Li, Renhua; Pinto, Donald; Orwat, Michael J.; Galemmo, Robert A.; Fevig, John M.; Teleha, Christopher A.; Alexander, Richard; Smallwood, Angela; Rossi, Karen A.; Wright, Matthew; Bai, Stephen A.; He, Kan; Luettgen, Joseph M.; Wong, Pancras C.; Knabb, Robert M.; Wexler, Ruth R.

doi:10.1021/jm020578e

Cited by 87 publications

(58 citation statements)

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“…Extensive preclinical and clinical studies show that inhibition of factor Xa is effective in both venous and arterial thrombosis (Pinto et al, 2001;Lam et al, 2003;Walenga et al, 2003). In animal models a better therapeutic index (antithrombotic efficacy versus antihemostatic effects) has been shown for direct factor Xa inhibitors compared with direct thrombin inhibitors (Leadley, 2001;Wong et al, 2002aWong et al, ,b, 2007.…”

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confidence: 99%

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Zhang¹,

Raghavan²,

Chen³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Razaxaban is a selective, potent, and orally bioavailable inhibitor of coagulation factor Xa. The molecule contains a 1,2-benzisoxazole structure. After oral administration of [ 14 C]razaxaban to intact and bile duct-cannulated rats (300 mg/kg) and dogs (20 mg/kg), metabolism followed by biliary excretion was the major elimination pathway in both species, accounting for 34 to 44% of the dose, whereas urinary excretion accounted for 3 to 13% of the dose. Chromatographic separation of radioactivity in urine, bile, and feces of rats and dogs showed that razaxaban was extensively metabolized in both species. Metabolites were identified on the basis of liquid chromatography/tandem mass spectrometry and comparison with synthetic standards. Among the 12 metabolites identified, formation of an isoxazole-ring opened benzamidine metabolite (M1) represented a major metabolic pathway of razaxaban in rats and dogs. However, razaxaban was the major circulating drug-related component (>70%) in both species, and M1, M4, and M7 were minor circulating components. In addition to the in vivo observations, M1 was formed as the primary metabolite in rat and dog hepatocytes and in the rat liver cytosolic fraction. The formation of M1 in the rat liver fraction required the presence of NADH. Theses results suggest that isoxazole ring reduction, forming a stable benzamidine metabolite (M1), represents the primary metabolic pathway of razaxaban in vivo and in vitro. The reduction reaction was catalyzed by NADH-dependent reductase(s) in the liver and possibly by intestinal microflora on the basis of the recovery of M1 in feces of bile duct-cannulated rats.

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confidence: 99%

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Zhang¹,

Raghavan²,

Chen³

et al. 2007

Drug Metab Dispos

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“…The first leads contained isoxazoline or isoxazole derivatives, such as benzamidine, guanidine, or napthylamidine, which are thought to mimic Glu-Gly-Arg, the sequence in prothrombin that is recognized by fXa. 42 The first such compound was DX-9065a, which contained highly basic amidine groups as nonpeptidic mimetics of the Arg residue in the prothrombin recognition sequence. 43 Because it exploited interactions with the S4 and S1 subsites of the active site (Figure 2), DX-9065a was specific for fXa and inhibited the enzyme with a K i value of 46 nmol/L.…”

Section: Development Of Synthetic Oral Direct Fxa Inhibitorsmentioning

confidence: 99%

“…47 Although the results of the study were promising, development of DX-9065a was halted because the oral bioavailability of the drug in humans was only 2% to 3% because of its highly basic amidine content. 42 Nonetheless, DX-9065a provided the groundwork for future orally active fXa inhibitors.…”

Section: Development Of Synthetic Oral Direct Fxa Inhibitorsmentioning

confidence: 99%

Oral Direct Factor Xa Inhibitors

Fredenburgh

Weitz

2012

Circulation Research

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Vitamin K antagonists, such as warfarin, have been the mainstay of oral anticoagulation for many decades. Although effective, warfarin has numerous limitations, including a variable dose requirement from patient to patient because of differences in dietary vitamin K intake, common genetic polymorphisms, and multiple drug interactions that affect its pharmacodynamics and metabolism. Consequently, warfarin requires frequent monitoring to ensure that a therapeutic anticoagulant effect has been achieved because excessive anticoagulation can lead to bleeding, and because insufficient anticoagulation can result in thrombosis. Such monitoring is burdensome for patients and physicians and is costly for the health care system. These limitations have prompted the development of new oral anticoagulants that target either factor Xa or thrombin. Although the path to the development of these drugs has been long, the new drugs are at least as effective and safe as warfarin, but they streamline clinical care because they can be administered in fixed doses without routine coagulation monitoring. This article focuses on rivaroxaban, apixaban, and edoxaban, the oral factor Xa inhibitors in the most advanced stages of development. After 20 years of discovery research, these agents are already licensed for several indications. Thus, the long path to finding replacements for warfarin has finally reached fruition. Therefore, development of the oral factor Xa inhibitors represents a translational science success story.

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“…The yellow precipitate was filtered and washed with diethyl ether (2 100 mL) providing the desired compound 3 as a yellow solid (135 mg, 95 %). N,N-Di-(4-aminobutyl)-AmB (4): To a solution of 2,2,2-trifluoro-N-(4-oxobutyl)acetamide [73] (160 mg, 0.860 mmol) and AmB (1) (200 mg, 0.216 mmol) in DMF (2.00 mL) was added NaBH 3 CN (54.0 mg, 0.860 mmol) followed by a drop of conc. HCl.…”

Section: By4741mentioning

confidence: 99%

Synthesis and In Vitro Biological Properties of Novel Cationic Derivatives of Amphotericin B

Paquet¹,

Volmer²,

Carreira³

2008

Chemistry A European J

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Novel cationic amphotericin B derivatives as highly potent antifungal agents are reported. These semi-synthetic derivatives of amphotericin B were elaborated through a series of modifications both on the nitrogen atom of the mycosamine and on the C-16 carboxylic acid moiety. The antifungal activity of the new conjugates was tested against Saccharomyces cerevisiae and also against nine different strains of Candida albicans and Candida glabrata, including an amphotericin resistant strain. High potency was observed in the case of polyamine derivatives bearing two 3-aminopropyl chains on the mycosamine. The evaluation of the biological properties also included the determination of the hemolytic activity of the compounds by measuring the EH50 values.

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Structure-Based Design of Novel Guanidine/Benzamidine Mimics: Potent and Orally Bioavailable Factor Xa Inhibitors as Novel Anticoagulants

Cited by 87 publications

References 14 publications

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Reductive Isoxazole Ring Opening of the Anticoagulant Razaxaban Is the Major Metabolic Clearance Pathway in Rats and Dogs

Oral Direct Factor Xa Inhibitors

Synthesis and In Vitro Biological Properties of Novel Cationic Derivatives of Amphotericin B

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