Tetrahydrothienopyridine derivatives as novel GPIIb/IIIa antagonists

Katano, Kiyoaki; Shitara, Eiki; Shimizu, M.; Sasaki, Kazue; Miura, Tomoaki; Isomura, Yasuko; Kawaguchi, Mariko; Ohuchi, Shokichi; Tsuruoka, Takashi

doi:10.1016/0960-894x(96)00476-3

Cited by 9 publications

(6 citation statements)

References 16 publications

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“…By the use of improved methods and modified experimental procedures the scope of easily obtainable 2-aminothiophenes ultimately spread. More complex starting substrates, especially starting carbonyl derivatives, such as azepinones 69 , indanones 39 , pyranones 70 , α-and β-tetralones 71 and many other types [72][73][74][75] undergo the modified Gewald reaction.…”

Section: Modifications Of the Gewald Reactionmentioning

confidence: 99%

“…Because the structure-based drug design program through substituted 2-aminothiophenes has been investigated broadly, up to this date there are many other research works dealing with the synthesis, pharmacology and application of thiophene-based structures in medicinal chemistry. 7,[12][13][14]36,37,51,69,100,101,[119][120][121][122][123][124][125][126][127] It is no doubt, that this area of Gewald-like thiophene derivatives exhibits the highest progress in a scope and utilization.…”

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confidence: 99%

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Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Puterová¹,

Krutošíková²,

Végh³

2010

Arkivoc

177

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Chemistry of 2-aminothiophenes is arguably one of the most extensive and dynamic field of present-day thiophene research. Since 1961 when first report on the Gewald reaction was reported it became a universal method for synthesis of substituted 2-aminothiophenes and has gained prominence in recent times. The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. This review summarizes the synthetic strategies for substituted 2-aminothiophenes. Consequently, details about the proposed mechanism of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications.

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Section: Modifications Of the Gewald Reactionmentioning

confidence: 99%

mentioning

confidence: 99%

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Puterová¹,

Krutošíková²,

Végh³

2010

Arkivoc

177

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“…After oxidation of 15, the resulting aldehyde 16 and N-Boc-piperidone were condensed by aldol reaction with LDA and then treated with concentrated HCl to give tetrahydropyrropyridine drothiazolo [5,4-c]pyridine was protected with di-tertbutyl dicarbonate then treated with n-BuLi and CO 2 to give 33. 5-Boc-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid and 6-Boc-4,5,6,7-tetrahydrothieno-[2,3-c]pyridine-2-carboxylic acid were prepared with the method reported by Katano et al 17 Preparation of 1-(6-chloronaphthalen-2-yl)sulfonylpiperazine (36) is shown in Scheme 7. (6-Chloronaphthalen-2-yl)sulfonyl chloride (35) was synthesized via β-sulfonylation and successive chlorination of 2-chloronaphthalene (34).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Conformational Analysis of a Non-Amidine Factor Xa Inhibitor That Incorporates 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 Binding Element

Haginoya¹,

Kobayashi²,

Komoriya³

et al. 2004

J. Med. Chem.

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Our exploratory study was based on the concept that a non-amidine factor Xa (fXa) inhibitor is suitable for an orally available anticoagulant. We synthesized and evaluated a series of N-(6-chloronaphthalen-2-yl)sulfonylpiperazine derivatives incorporating various fused-bicyclic rings containing an aliphatic amine expected to be S4 binding element. Among this series, 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine type 61 displayed orally potent anti-fXa activity and evident prolongation of prothrombin time (PT) with the moderate bioavailability in rats. The X-ray crystal analysis afforded an obvious binding mode that 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine and 6-chloronaphthalene respectively bound to S4 and S1 subsites. In this X-ray study, we discovered a novel intramolecular S-O close contact. Ab initio energy calculations of model compounds deduced that conformers with the most close S-O proximity were most stable. The Mulliken population analysis proposed that this energy profile was caused by both of electrostatic S-O affinity and N-O repulsion. The results of these calculations and X-ray analysis suggested a possibility that the restricted conformation effected the affinity to S4 subsite of fXa.

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“…Condensation of piperidine with thiophene ring keeping two methylene distances in 68 gave rise to 69, which showed even more potent inhibitory activity. Optimization of the carboxyl terminus of 69 indicated that the position of oxyacetic acid moiety played an important role in acquiring inhibitory activity and the para-position to ketone group was more potent than metaposition, for example, compound 70 (IC 50 >10 μM, human PRP/ADP) [66].…”

Section: Lead Compound: Compound From Htsmentioning

confidence: 99%

Progress in the Research of GPIIb/IIIa Antagonists

et al. 2015

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This review covers the recent advances in the development of small RGD (Arg-Gly-Asp sequence) containing peptides and their mimetics as potential antithrombotic agents. Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists include monoclonal antibodies, RGD peptides, peptide hybrids and nonpeptide mimetics. The current trend in the development of nonpeptide mimetics is clearly directed toward orally active and safe antithrombotic drug candidates. But several nonpeptide mimetics, being evaluated for their oral activity in human clinical trials, are currently not approved for clinical use due to poor safety profile. It is expected that newer and more effective nonpeptide mimetics will be developed in the near future.

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Tetrahydrothienopyridine derivatives as novel GPIIb/IIIa antagonists

Cited by 9 publications

References 16 publications

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Synthesis and Conformational Analysis of a Non-Amidine Factor Xa Inhibitor That Incorporates 5-Methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine as S4 Binding Element

Progress in the Research of GPIIb/IIIa Antagonists

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