ANTITHROMBOTIC ACTIONS OF SELECTIVE INHIBITORS OF BLOOD COAGULATION FACTOR Xa IN RAT MODELS OF THROMBOSIS

Wong, Pancras C.; Crain, Earl J.; Nguan, Oliver; Watson, Carol A.; Racanelli, Adrienne L.

doi:10.1016/0049-3848(96)00112-0

Cited by 42 publications

(25 citation statements)

References 22 publications

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“…Silk's knot strength, handling characteristics and ability to lay low to the tissue surface make it a popular suture in cardiovascular applications where bland tissue reactions are desirable for the coherence of the sutured structures [36]. However, black braided silk is thrombotic following implantation within ateriovessels [46,47]. Using a rat model, Dahike et al [47] showed black braided silk binds fibrin and platelets within 3 days in vivo following implantation into arteriovessels.…”

Section: Concernsmentioning

confidence: 99%

Silk-based biomaterials

et al. 2003

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Silk from the silkworm, Bombyx mori, has been used as biomedical suture material for centuries. The unique mechanical properties of these fibers provided important clinical repair options for many applications. During the past 20 years, some biocompatibility problems have been reported for silkworm silk; however, contamination from residual sericin (glue-like proteins) was the likely cause. More recent studies with well-defined silkworm silk fibers and films suggest that the core silk fibroin fibers exhibit comparable biocompatibility in vitro and in vivo with other commonly used biomaterials such as polylactic acid and collagen. Furthermore, the unique mechanical properties of the silk fibers, the diversity of side chain chemistries for 'decoration' with growth and adhesion factors, and the ability to genetically tailor the protein provide additional rationale for the exploration of this family of fibrous proteins for biomaterial applications. For example, in designing scaffolds for tissue engineering these properties are particularly relevant and recent results with bone and ligament formation in vitro support the potential role for this biomaterial in future applications. To date, studies with silks to address biomaterial and matrix scaffold needs have focused on silkworm silk. With the diversity of silk-like fibrous proteins from spiders and insects, a range of native or bioengineered variants can be expected for application to a diverse set of clinical needs. r

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Section: Concernsmentioning

confidence: 99%

Silk-based biomaterials

et al. 2003

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“…[23][24][25][26] Direct inhibition of FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [27][28][29][30][31][32][33] In a previous paper, 4) we reported the synthesis and evaluation of compounds in a series of spiro [5H-oxazolo[3,2-a] (Table 1).…”

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Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors V. A Series of New Derivatives Containing a Spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one Scaffold

Saitoh

Mukaihira

Nishida

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Factor Xa (FXa), a trypsin-like serine protease, occupies the central position that links the intrinsic and extrinsic mechanisms in the blood coagulation cascade. FXa is known to activate prothrombin to thrombin. Thrombin has several procoagulant functions, including the activation of platelets, feedback activation of other coagulation factors, and conversion of fibrinogen to insoluble fibrin clots.6-10) Comparison of hirudin 11-15) (a thrombin inhibitor) and tick anticoagulant peptide [16][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] Direct inhibition of FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [27][28][29][30][31][32][33] In a previous paper, 4) we reported the synthesis and evaluation of compounds in a series of spiro [5H-oxazolo[3,2-a] (Table 1).These differences will affect the overall conformation of the compound, and differences in conformation between N,N-spiro acetal and N,O-spiro acetal might affect FXa inhibitory activity. In addition, differences in basicity between N,N-spiro acetal and N,O-spiro acetal might work on FXa inhibitory activity. ChemistryFirst, the keto-ester 5, an acyclic precursor, was prepared as shown in Chart 1.Ethyl glycinate 1 was converted by ring opening glycidyl methyl ether 2 to the corresponding amino-alcohol. The amino-alcohol was treated with benzyl chloroformate in THF-H 2 O in the presence of sodium carbonate with an Nprotected amino-alcohol 3 obtained in good yield. In the next step, the amino-alcohol 3 was oxidized to the keto-ester 5 by the 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate 4-NaClO oxidation method. was allowed to react with keto-ester 5 in toluene, the key intermediate 7 containing a N,N-spiro acetal structure on the Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-Uenohara, Gotemba, Shizuoka 412-8524, Japan. Received June 10, 2006; accepted September 2, 2006; published online September 5, 2006 We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC 50 ‫16.0؍‬ nM, M58169: IC 50 ‫85.0؍‬ nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).

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“…[21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) 4--2-piperazinecarboxylic acid were found to be potent inhibitors of FXa (IC 50 ϭ60 nM, 31 nM, 6 nM, respectively) with high selectivity for FXa over trypsin and thrombin.In more recent investigations, fixation of the conformation of testing compounds is believed to affect the strength of interaction between such compounds and the target enzyme. Accordingly, in the next stage of investigation our interest was focused on the synthesis of compounds containing a rigid structure in the central part of the compound (2, 3), and on comparison of the inhibitory activities of the compounds thus synthesized for FXa with those of previously reported compounds.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors IV. A Series of New Derivatives Containing a Spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one Skeleton

Nishida

Mukaihira

Saitoh

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Factor Xa (FXa), a trypsin-like serine protease, holds the central position that links the intrinsic and extrinsic mechanisms in the blood coagulation cascade. FXa is known to activate prothrombin to thrombin. Thrombin has several procoagulant functions that include the activation of platelets, feedback activation of other coagulation factors, and conversion of fibrinogen to insoluble fibrin clots. [4][5][6][7][8] Comparison of hirudin 9-13) (a thrombin inhibitor) and tick anticoagulant peptide [14][15][16][17][18][19][20] (a FXa inhibitor) suggests that inhibition of FXa may result in less bleeding risk, leading to a more favorable safety/efficacy ratio. [21][22][23][24] Direct inhibition to FXa has therefore emerged as an attractive strategy for the discovery of novel antithrombotic agents. [25][26][27][28][29][30][31] In preceding papers, 1,2) we reported the synthesis and evaluation of compounds in a series of 1-arylsulfonyl-3-piperazinone derivatives, of which M55113 (1) 4--2-piperazinecarboxylic acid were found to be potent inhibitors of FXa (IC 50 ϭ60 nM, 31 nM, 6 nM, respectively) with high selectivity for FXa over trypsin and thrombin.In more recent investigations, fixation of the conformation of testing compounds is believed to affect the strength of interaction between such compounds and the target enzyme. Accordingly, in the next stage of investigation our interest was focused on the synthesis of compounds containing a rigid structure in the central part of the compound (2, 3), and on comparison of the inhibitory activities of the compounds thus synthesized for FXa with those of previously reported compounds. A molecule with a spiro structure in between the piperidine moiety and piperazine moiety was therefore designed as the next candidate for further development of FXa inhibitor. The present paper concerns the synthesis of a series of compounds 4 with a spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4Ј-piperidin]-5-one skeleton, together with the FXa inhibitory activities of these new compounds. ChemistryFirst, acyclic precursor 9 was prepared as shown in Chart 1. Sulfonylamidation of glycine ethyl ester hydrochloride (5) with 6-chloro-2-naphthalenesulfonyl chloride (6) under traditional conditions yielded the corresponding naphthalenesulfonylamide 7. When 7 was treated with 1-acetoxy-3-chloroacetone (8) in DMF in the presence of potassium carbonate, 9 was obtained in good yield as expected.When 4-(aminomethyl)-1-benzyl-4-piperidinol (10) was allowed to react with acyclic precursor 9 under acidic conditions, a product 11 containing a spiro N,O-acetal structure on the piperazinone ring was obtained, as expected.The reaction pathway of the formation of the spiro skeleton from 9 and 10 is illustrated in Chart 2. In the first step, a Schiff base was formed by dehydration between a carbonyl group in 9 and a primary amino group in 10. Subsequent nucleophilic addition of a hydroxyl group to an azomethine Discovery Research Center, Mochida Pharmaceutical Co., Ltd.; 722 Jimba-aza-uenohara, Gotemba, Shizuoka 412-852...

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ANTITHROMBOTIC ACTIONS OF SELECTIVE INHIBITORS OF BLOOD COAGULATION FACTOR Xa IN RAT MODELS OF THROMBOSIS

Cited by 42 publications

References 22 publications

Silk-based biomaterials

Silk-based biomaterials

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors V. A Series of New Derivatives Containing a Spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one Scaffold

Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors IV. A Series of New Derivatives Containing a Spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4'-piperidin]-5-one Skeleton

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