Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids

Misra, Aalok; Kumar, Kaushlendra; Jain, Manish; Bajaj, Kirti; Shandilya, Shyamali; Srivastava, Smriti; Shukla, Pragya; Barthwal, Manoj Kumar; Dikshit, Madhu; Dikshit, Dinesh K.

doi:10.1016/j.ejmech.2016.01.019

Cited by 10 publications

(15 citation statements)

References 17 publications

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“…Coagulation parameters, prothrombin time [21], activated partial thromboplastin time (aPTT) and thrombin time (TT) were measured in plasma as per manufacturer's instructions using a Semi automated Coagulometer (Start4, Young Instruments, Stago, France) [38].…”

Section: Coagulation Parametersmentioning

confidence: 99%

“…The beads were washed, re-suspended in Laemmelli buffer, denatured at 95 0 C for 5 minutes, and subsequently analyzed by immunoblotting [34,38].…”

Section: Immunoprecipitationmentioning

confidence: 99%

“…Platelets were stimulated with collagen, and the reaction was stopped by adding 4X Laemmli buffer [39] (containing 10 µg/ml aprotinin, 1 mM PMSF, 10 µg/ml leupeptin, 10 mM NaF, 1 mM sodium orthovanadate). The lysates were boiled for 3 minutes [34,38], and centrifuged at 12,000 ×g for 5 minutes. Samples containing 30-40 µg of protein were subjected to SDS-PAGE and immunoblotting as described previously [34,38].…”

Section: Immunoblottingmentioning

confidence: 99%

“…The lysates were boiled for 3 minutes [34,38], and centrifuged at 12,000 ×g for 5 minutes. Samples containing 30-40 µg of protein were subjected to SDS-PAGE and immunoblotting as described previously [34,38].…”

Section: Immunoblottingmentioning

confidence: 99%

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Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Misra

Prakash

Aggarwal

et al. 2018

Biochemical Pharmacology

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Pharmacological inhibition of platelet collagen interaction is a promising therapeutic strategy to treat intra-vascular thrombosis. S007-867 is a novel synthetic inhibitor of collagen-induced platelet aggregation. It has shown better antithrombotic protection than aspirin and clopidogrel with minimal bleeding tendency in mice. The present study is aimed to systematically investigate the antithrombotic efficacy of S007-867 in comparison to aspirin and clopidogrel in vivo and to delineate its mechanism of action in vitro. Aspirin, clopidogrel, and S007-867 significantly reduced thrombus weight in arterio-venous (AV) shunt model in rats. In mice, following ferric chloride induced thrombosis in either carotid or mesenteric artery; S007-867 significantly prolonged the vessel occlusion time (1.2-fold) and maintained a sustained blood flow velocity for >30 min. Comparatively, clopidogrel showed significant prolongation in TTO (1.3-fold) while aspirin remained ineffective. Both S007-867 and aspirin did not alter bleeding time in either kidney or spleen injury models, and thus maintained hemostasis, while clopidogrel showed significant increase in spleen bleeding time (1.7-fold). The coagulation parameters namely thrombin time, prothrombin time or activated partial thromboplastin time remained unaffected even at high concentration of S007-867 (300 µM), thus implying its antithrombotic effect to be primarily platelet mediated. S007-867 significantly inhibited collagen-mediated platelet adhesion and aggregation in mice ex-vivo. Moreover, when blood was perfused over a highly thrombogenic combination of collagen mimicking peptides like CRP-GFOGER-VWF-III, S007-867 significantly reduced total thrombus volume or ZV (53.4 ± 5.7%). Mechanistically, S007-867 (10-300 μM) inhibited collagen-induced ATP release, thromboxane A (TxA) generation, intra-platelet [Ca] flux and global tyrosine phosphorylation including PLCγ2. Collectively the present study highlights that S007-867 is a novel synthetic inhibitor of collagen induced platelet activation, that effectively maintains blood flow velocity and delays vascular occlusion. It inhibits thrombogenesis without compromising hemostasis. Therefore, S007-867 may be further developed for the treatment of thrombotic disorders in clinical settings.

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Section: Coagulation Parametersmentioning

confidence: 99%

“…The beads were washed, re-suspended in Laemmelli buffer, denatured at 95 0 C for 5 minutes, and subsequently analyzed by immunoblotting [34,38].…”

Section: Immunoprecipitationmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

Section: Immunoblottingmentioning

confidence: 99%

See 2 more Smart Citations

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Misra

Prakash

Aggarwal

et al. 2018

Biochemical Pharmacology

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“…Furthermore, 1,4-diazabicyclo[3.3.1]nonane derivatives are reported to exhibit high in vivo affinity and selectivity for the dopamine transporter (DAT) blockers [14,15]. 3,7-Diazabicyclo[3.3.1]nonanes are reported to be useful in the treatment of cardiac arrhythmias [16], and exhibited anti-platelet, antithrombotic activities [17], as well as high affinities at various nicotinic acetylcholine receptors (nAChRs) [18,19,20]. 3,9-Diazabicyclo[3.3.1]nonanes showed the 5-HT3 receptor antagonist [21] and opioid δ and μ-receptor activities [22,23].…”

Section: Introductionmentioning

confidence: 99%

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

et al. 2019

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Reactions of a series of 3-oxo-2-arylhydrazonopropanal derivatives with two molar ratio of ammonium acetate afforded a library of tetrasubstituted 2,3,6,7,9-pentaazabicyclo[3.3.1]nona- 3,7-diene derivatives in good to excellent isolated yields. The reaction was activated with triethylamine catalyst under three different heating modes: thermal, ultrasonic and microwave irradiating conditions in ethanol solvent. The structures of the isolated products were fully characterized by spectral and analytical data as well as X-ray single crystal of selected examples.

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Design, Synthesis, and Evaluation of Novel L-Pyroglutamic Acid Derivatives as Potent Antifungal Agents

Sun

Zhu

et al. 2021

Chem Nat Compd

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A series of novel L-pyroglutamate containing 1,2,3-triazole ring substructures was synthesized and characterized by adopting an appropriate synthetic scheme. The effect of different substituents on the triazole ring at the ortho-, meta-and para-positions of the benzene ring was evaluated for the inhibition of zoospore release activity against Phytophthora infestans. Among the triazole analogs of L-pyroglutamate, compounds with a phenyl or benzyl group on the triazole ring at the meta-position of the benzene ring showed potent antifungal activity. Results indicated that some of the L-pyroglutamic acid derivatives possessed antifungal activity against Phytophthora infestans.

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Synthesis and evaluation of dual antiplatelet activity of bispidine derivatives of N-substituted pyroglutamic acids

Cited by 10 publications

References 17 publications

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Anti-thrombotic efficacy of S007-867: Pre-clinical evaluation in experimental models of thrombosis in vivo and in vitro

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

Design, Synthesis, and Evaluation of Novel L-Pyroglutamic Acid Derivatives as Potent Antifungal Agents

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