DX-9065a, a New Synthetic, Potent Anticoagulant and Selective Inhibitor for Factor Xa

Hara, Tsuyoshi; Yokoyama, Asako; Ishiga, Hiroaki; Yokoyama, Yukio; Nagahara, Takayasu; Iwamoto, Masahiro

doi:10.1055/s-0038-1642436

Cited by 169 publications

(154 citation statements)

References 25 publications

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“…1). Daiichi compound DX9065a ((+)-2-[4-[((3S)-l-acetimidoyl-3-pyrrodinyl)oxy]phenyl]-3-(7-amidino-2-napthyl)propionic acid) exhibits a K~ of 41 nM for factor Xa, no activity against thrombin and displays some oral activity [11]. The inhibitor has been modelled to the active sites of factor Xa, thrombin and human trypsin [10,[12][13].…”

Section: Introductionmentioning

confidence: 99%

Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin

1995

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Crystal structures of DX9065a and a related bisamidino-aryl inhibitor specific for the blood-clotting factor Xa have been solved in complex with bovine ~-trypsin to a resolution of 1.9 A. Each inhibitor exhibits an extended conformation along the active site, in contrast to the compact folded structures observed for thrombin specific inhibiturs. Few direct contacts (predominantly in the S1 pocke0 are made between trypsin and the inhibitors. Transfer of the inhibitors to the active site of factor Xa suggests a three-site interaction: salt bridge formation at the base of the primary specificity pocket, extensive hydrophobie surface burial and a weak electrostatic interaction between the distal basic component of the inhibitor and an electronegative cavity of factor Xa formed by three backbone carbonyl oxygens. Additivity of these three interactions is the basis for the observed strong inhibition of factor Xa and provides a framework for the design of novel factor Xa inhibitors. A propionic acid group of the inhibitor would clash with the thrombin specific '60-insertion loop', thus conferring selectivity against thrombin.

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Section: Introductionmentioning

confidence: 99%

Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin

1995

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“…The accompanying paper (8) demonstrates the differential actions on thrombin generation by two different anticoagulant protease inhibitors DX-9065a (9) and argatroban (10). Both theoretical and experimental approaches (8) revealed that the thrombin inhibitor, argatroban, yielded a stronger inhibitory effect on thrombin generation than the fXa inhibitor, DX-9065a, while the two inhibitors prolonged clot time to a similar extent when coagulation was triggered by the extrinsic pathway stimuli of the same intensity.…”

Section: Tafimentioning

confidence: 99%

Studies on the Different Modes of Action of the Anticoagulant Protease Inhibitors DX-9065a and Argatroban

Nagashima¹

2002

Journal of Biological Chemistry

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The accompanying paper (Nagashima, H. (2002) J. Biol. Chem. 277, 50439 -50444) has demonstrated that argatroban can yield a stronger inhibitory effect on thrombin generation than DX-9065a during extrinsic pathway-stimulated human plasma coagulation, while these anticoagulant compounds have comparable abilities to prolong clot time. Since thrombin generation is known to be an important determinant for fibrinolytic resistance of clots formed during coagulation, the two compounds are compared by tissue plasminogen activator-induced clot lysis assays. The results demonstrated that, in the presence of thrombomodulin, argatroban dose dependently accelerated fibrinolysis of the clots, whereas DX-9065a did not. The activation of thrombin activatable fibrinolysis inhibitor (TAFI) determined in separate assays reflected the differential influence on thrombin generation by these compounds. Moreover, TAFI activation correlated closely with the fibrinolytic resistance observed during tissue plasminogen activator-induced clot lysis. This study demonstrates the differential effects of DX-9065a and argatroban on thrombin generation, which in turn results in a differential acceleration of fibrinolysis as well as TAFI activation in the clots formed under the influence of these compounds. The data implicate a possible difference in the antifibrinolytic properties of clots formed during treatment with these compounds.Thrombin plays a central role in thrombosis and hemostasis. While only a small amount of prothrombin is activated at the moment of clotting, the remaining prothrombin is activated predominantly after clot formation (1). These observations are consistent with the recently proposed notion (2) that activation of the extrinsic pathway is responsible for the rapid generation of a small amount of thrombin, which is sufficient for clot formation; however, activation of the intrinsic pathway is responsible for a massive production of thrombin mostly after clot formation, which effectively augments the antifibrinolytic properties of the clot. Such an intrinsic pathway-mediated thrombin burst is critically dependent on a feedback activation mechanism mediated by thrombin-catalyzed activation of factor XI (3, 4). TAFI1 is a zymogen that plays a key role in the regulation of fibrinolysis. During coagulation, TAFI is proteolytically activated by thrombin in a TM-dependent manner to its active form, TAFIa, which inhibits fibrinolysis by removing the carboxyl-terminal lysine and arginine residues from partially degraded fibrin (5, 6). As activation of TAFI requires exposure to relatively high concentrations of thrombin, the intrinsic pathway-mediated thrombin generation plays a pivotal role in the regulation of fibrinolysis (7).The accompanying paper (8) demonstrates the differential actions on thrombin generation by two different anticoagulant protease inhibitors DX-9065a (9) and argatroban (10). Both theoretical and experimental approaches (8) revealed that the thrombin inhibitor, argatroban, yielded a stronger inhibitory effect on...

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“…Na química medicinal, muitas substâncias contendo este grupo funcional têm apresentado atividade contra vários agentes patogênicos como Giardia lamblia 5 , Leishmania sp [6][7][8][9] , Pneumocystis carinii [10][11][12][13][14] , Candida albicans 15,16 , Cryptococcus neoformans 15,16 , 17 , Trypanosoma sp [18][19][20][21] , Cryptosporidium sp 22 , Acanthamoeba polyphaga 23 e Plasmodium sp 24 . Além disso, o grupo amidina está presente em diversos compostos com atividade antitrombótica [25][26][27][28] . Na química de heterociclos, amidinas são intermediários muito utilizados nas sínteses de importantes sistemas [29][30][31] , tais como pirimidinas [32][33][34] , oxazóis 35 , triazinas 36 e tiazóis 37 .…”

Section: Introductionunclassified

Principais métodos de síntese de amidinas

Santos¹,

Bernardino²,

Souza³

2006

Quím. Nova

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Recebido em 8/6/05; aceito em 6/1/06; publicado na web em 6/7/06 SYNTHETIC APPROACHES TO AMIDINES. The amidine functional group is found in a wide range of natural products and is biologically active against several pathogens. In addition, amidines have long been regarded as useful intermediates in the synthesis of heterocyclic compounds. Consequently, a great number of methods have been developed for the preparation of amidines. Pinner's method is the most commonly used. Conventional methods include: -the addition of metal amides or amines to nitriles, the addition of amines to imido esters and the condensation of amides with amines in the presence of halogenating reagents. In this report, the main methods for synthesis of amidines will be described.

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DX-9065a, a New Synthetic, Potent Anticoagulant and Selective Inhibitor for Factor Xa

Cited by 169 publications

References 25 publications

Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin

Crystal structures of factor Xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor Xa and selectivity against thrombin

Studies on the Different Modes of Action of the Anticoagulant Protease Inhibitors DX-9065a and Argatroban

Principais métodos de síntese de amidinas

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