RESUMO
The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73.
Assuntos
5'-Nucleotidase/antagonistas & inibidores , Apirase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Tienopiridinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas Ligadas por GPI/antagonistas & inibidores , Humanos , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/química , Ticlopidina/farmacologiaRESUMO
A series of novel functionalized methyl 3-(hetero)arylthieno[3,2-b]pyridine-2-carboxylates 2a-2h were synthesized by C-C Pd-catalyzed Suzuki-Miyaura cross-coupling of methyl 3-bromothieno[3,2-b]pyridine-2-carboxylate with (hetero)aryl pinacol boranes, trifluoro potassium boronate salts or boronic acids. Their antitumoral potential was evaluated in two triple negative breast cancer (TNBC) cell lines-MDA-MB-231 and MDA-MB-468, by sulforhodamine B assay. Their effects on the non-tumorigenic MCF-12A cells were also evaluated. The results demonstrated that three compounds caused growth inhibition in both TNBC cell lines, with little or no effect against the non-tumorigenic cells. The most promising compound was further studied concerning possible effects on cell viability (by trypan blue exclusion assay), cell proliferation (by bromodeoxyuridine assay) and cell cycle profile (by flow cytometry). The results demonstrated that the GI50 concentration of compound 2e (13 µM) caused a decreased in MDA-MB-231 cell number, which was correlated with a decreased in the % of proliferating cells. Moreover, this compound increased G0/G1 phase and decreased S phases, when compared to control cells (although was not statistic significant). Interestingly, compound 2e also reduced tumor size using an in ovo CAM (chick chorioallantoic membrane) model. This work highlights the potential antitumor effect of a novel methyl 3-arylthieno[3,2-b]pyridine-2-carboxylate derivative.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Tienopiridinas/síntese química , Tienopiridinas/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Membrana Corioalantoide/cirurgia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/patologia , Estrutura Molecular , Transplante de Neoplasias , Relação Estrutura-Atividade , Tienopiridinas/química , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones to produce 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-diones has been developed, utilizing ambient air as the sole reactant. N-H Imines are formed as the major products, and excellent functional group tolerance and conversion on gram-scale without the need for chromatographic purification allow for facile late-stage diversification of the aminothienopyridinone scaffold. Several analogs exhibit potent in vitro inhibition of the cancer-associated protein tyrosine phosphatase PTP4A3, and the SAR supports an exploratory docking model.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Piridonas/química , Piridonas/farmacologia , Tienopiridinas/química , Tienopiridinas/farmacologia , Aminação , Humanos , Luz , Modelos Moleculares , Proteínas de Neoplasias/metabolismo , Oxirredução , Proteínas Tirosina Fosfatases/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of thieno[3,2-d]pyrimidine derivatives as phosphatidylinositol 3-kinase (PI3K) inhibitors was designed using the combination strategy. The synthesis and biological evaluation of the derivatives demonstrated their potent inhibition of PI3K, culminating in the discovery of 7 and 21. Determination of a co-crystal structure of 7 complexed with PI3Kα provided the structural basis for the high enzymatic activity. Furthermore, cellular investigation of compounds 7 and 21 revealed that they efficiently suppressed cancer cell lines proliferation through inhibition of intracellular PI3K/AKT/mammalian target of rapamycin pathway. The results provided potent simplified inhibitors of PI3K with a promising overall profile and a chemical series for further optimization to progress into vivo experiments.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Tienopiridinas/química , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Dinâmica Molecular , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Tienopiridinas/metabolismo , Tienopiridinas/farmacologiaRESUMO
A series of pyridine and thieno[2,3-b]pyridine derivatives have been designed and synthesized as anticancer PIM-1 kinase inhibitors. Thirty-seven compounds were selected by NCI to be tested initially at a single dose (10⯵M) in the full NCI 60 cell line panel. Compound 5b showed potent anticancer activity and was tested twice in the five-dose assay which confirmed its potent antitumor activity (GI50 values 0.302-3.57⯵M) against all tested tumor cell lines except six cell lines where they showed moderate sensitivity. This compound was sent to NCI biological evaluation committee and still under consideration for further testing. In addition, the most active anticancer compounds in each series, 5b, 8d, 10c, 13h, and 15e, were evaluated for their PIM-1 kinase inhibitory activity. Compound 8d was the most potent one with IC50â¯=â¯0.019⯵M followed by 5b, 15e, 10c and 13h with IC50 values 0.044, 0.083, 0.128 and 0.479⯵M respectively. Moreover, docking study of the most active compounds in PIM-1 kinase active site was consistent with the in vitro activity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Tienopiridinas/química , Tienopiridinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Tienopiridinas/síntese químicaRESUMO
The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2-hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research.
Assuntos
Difosfato de Adenosina/efeitos adversos , Agregação Plaquetária/efeitos dos fármacos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Tienopiridinas/química , Animais , Tempo de Sangramento , Clopidogrel , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Estrutura Molecular , Cloridrato de Prasugrel/administração & dosagem , Cloridrato de Prasugrel/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Ticlopidina/administração & dosagem , Ticlopidina/análogos & derivados , Ticlopidina/farmacologiaRESUMO
Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80-250nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Tienopiridinas/química , Tienopiridinas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Neoplasias/tratamento farmacológico , Quinolinas/síntese química , Relação Estrutura-Atividade , Tienopiridinas/síntese químicaRESUMO
The fluorescence properties of the new potent antitumoral methyl 3-amino-6-(benzo[d]thiazol-2-ylamino)thieno[3,2-b]pyridine-2-carboxylate in solution and when encapsulated in several different nanoliposome formulations were investigated. The compound exhibits very reasonable fluorescence quantum yields and a solvent sensitive emission in several polar and non-polar media, despite not being fluorescent in protic solvents. Fluorescence anisotropy measurements of the compound incorporated into liposomes revealed that this thienopyridine derivative can be carried in the hydrophobic region of the lipid membrane. Liposome formulations including this antitumor compound are nanometric in size, with a diameter lower than 130 nm and generally low polydispersity, and are promising for future drug delivery developments. The interaction of the compound with bovine serum albumin (BSA) and the multidrug resistance protein MDR1 was monitored by FRET, the compound acting as an energy acceptor. It was observed that the drug had a lower interaction with the MDR1 protein than with the native form of BSA, which is an important result regarding applications of this antitumoral drug.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Tienopiridinas/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/química , Animais , Bovinos , Proteínas do Ovo/química , Fluorescência , Polarização de Fluorescência , Transferência Ressonante de Energia de Fluorescência , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipossomos/química , Estrutura Molecular , Nanoestruturas/química , Soroalbumina Bovina/química , Solventes/química , Espectrometria de FluorescênciaRESUMO
To identify new potent multidrug resistance modulators, we have synthesized a series of novel thieno[2,3-b]pyridines and furo[2,3-b]pyridines, and examined their structure-activity relationships. All synthesized compounds were tested to determine BCRP1, P-gp, and MRP1 inhibitor activity, and most potent MDR modulators were also screened for their toxicity, cytotoxicity and Ca(2+) channel antagonist activity. Among these compounds, thieno[2,3-b]pyridine (6r) was found to exhibit a potent P-gp inhibitory action with EC50 = 0.3 ± 0.2 µM, MRP1 inhibitory action with EC50 = 1.1 ± 0.1 µM and BCRP1 inhibitory action with EC50 = 0.2 ± 0.05 µM and may represent suitable candidate for further pharmacological studies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Tienopiridinas/química , Tienopiridinas/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/química , Bloqueadores dos Canais de Cálcio/metabolismo , Bloqueadores dos Canais de Cálcio/toxicidade , Canais de Cálcio/química , Canais de Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Camundongos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Músculo Liso/metabolismo , Células NIH 3T3 , Proteínas de Neoplasias/metabolismo , Ligação Proteica , Ratos , Relação Estrutura-Atividade , Tienopiridinas/metabolismo , Tienopiridinas/toxicidadeRESUMO
Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.
Assuntos
Antagonistas dos Receptores de Dopamina D2 , Piperazinas/síntese química , Piperidinas/síntese química , Receptores de Dopamina D2/agonistas , Tienopiridinas/síntese química , Animais , Células CHO , Cricetulus , AMP Cíclico/biossíntese , Agonismo Parcial de Drogas , Ligantes , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosforilação , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ensaio Radioligante , Receptores de Dopamina D2/metabolismo , Relação Estrutura-Atividade , Tienopiridinas/química , Tienopiridinas/farmacologiaRESUMO
An operationally simple approach for the stereoselective tandem synthesis of novel thiazolo fused naphthyridines and thienopyridines by the reaction of o-alkynylaldehydes with L-cystine methyl ester hydrochloride via Au(III)-catalyzed regioselective 6-endo-dig ring closure under mild reaction conditions is described. It is noteworthy that alkynes bearing an alkyl and a strong electron-withdrawing nitro group successfully afforded the desired products in good yields.
Assuntos
Aldeídos/química , Alcinos/química , Ouro/química , Naftiridinas/síntese química , Tiazóis/química , Tienopiridinas/síntese química , Catálise , Estrutura Molecular , Naftiridinas/química , Estereoisomerismo , Tienopiridinas/químicaRESUMO
In our previous study, a series of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives exhibited potent antiproliferative activities and an unique hepatocellular carcinoma (HCC)-specific anticancer activity was also observed. In further anti-inflammatory research, thienopyridine derivative 1a showed potent inhibition of nitric oxide (NO) production. So a series of thienopyridine analogues of 1a were synthesized and evaluated for anti-inflammatory activities. The structure-activity relationships (SARs) revealed that the most potent analogues 1f and 1o were identified as potent inhibitors of NO production with IC50 values of 3.30 and 3.24 µM, respectively. These results suggest that these 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives might potentially constitute a novel class of anti-inflammatory agents, which require further studies.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Tienopiridinas/química , Tienopiridinas/farmacologia , Anti-Inflamatórios/síntese química , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Relação Estrutura-Atividade , Tienopiridinas/síntese químicaRESUMO
A series of novel, potent 4-aminothienopyridine B-Raf kinase inhibitors was designed and synthesized using knowledge-based design. Compounds 5f, and 6k exhibited not only excellent potency in both enzyme assay (IC(50)=5.1, 16.6 nM) and cellular assay (IC(50)=0.2, 0.2 µM), but also had an outstanding selectivity profile against other kinases.
Assuntos
Aminopiridinas/química , Compostos de Fenilureia/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Tienopiridinas/química , Aminopiridinas/síntese química , Aminopiridinas/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos de Fenilureia/síntese química , Compostos de Fenilureia/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/metabolismoRESUMO
The article describes characterization of two liposome formulations containing thienopyridine derivatives, namely TP-58 and TP-67. By preparing the liposomes, the concentration of the two compounds in ultrapure water was increased up to three orders of magnitude. After i.v. administration of the liposomes in rats, the initial compound plasma concentrations were enhanced more than fifty times relative to that after i.g. administration of the compound suspensions. It was found out that the release rate of TP-67 from the liposome both in vitro and in vivo was not significantly different from that of TP-58. TP-58 was more lipophilic than TP-67 according to partition coefficiency, and TP-67 had greater polarity than TP-58 based on polar surface area (PSA). With DSC, it was found out that the interaction magnitude between TP-67 and the lipid bilayer was not significantly different from that between TP-58 and the lipid bilayer, which accounted for the similarity of the two compounds in release rate both in vitro and in vivo. It indicated liposome can be used as a potential carrier for broading the application of TP-58 and TP-67. Interaction between the thienopyridine derivatives and the lipid bilayer is probably the decisive factor for compound release from the liposomes.
Assuntos
Bicamadas Lipídicas/química , Lipossomos/administração & dosagem , Tienopiridinas/administração & dosagem , Animais , Química Farmacêutica/métodos , Feminino , Lipossomos/química , Lipossomos/farmacocinética , Camundongos , Ratos , Ratos Sprague-Dawley , Tienopiridinas/química , Tienopiridinas/farmacocinéticaRESUMO
The phosphoinositide specific-phospholipase C-γ (PLC-γ1 and 2) enzymes are plausible anticancer targets implicated in cell motility important to invasion and dissemination of tumour cells. A host of known PLC-γ2 inhibitors were tested against the NCI60 panel of human tumour cell lines as well as their commercially available structural derivatives. A class of thieno[2,3-b]pyridines showed excellent growth arrest with derivative 3 giving GI(50) = 58 nM for the melanoma MDA-MB-435 cell line. The PLC-γ2 is uniquely expressed in haematopoietic cells and the leukaemia tumour cell lines were growth restricted on average GI(50) = 275 nM by derivative 3 indicating a specific interaction with this isoform. Furthermore, a moderate growth inhibition was found for compound classes of indoles and 1H-pyrazoles. It is likely that the active compounds do not only inhibit the PLC-γ2 isoform but other PLCs as well due to their conserved binding site. The compounds tested were identified by applying the tools of chemoinformatics, which supports the use of in silico methods in drug design.
Assuntos
Inibidores Enzimáticos/farmacologia , Neoplasias/patologia , Fosfolipase C gama/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Indóis/metabolismo , Indóis/farmacologia , Simulação de Acoplamento Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Oxidiazóis/metabolismo , Oxidiazóis/farmacologia , Fosfolipase C gama/química , Fosfolipase C gama/metabolismo , Conformação Proteica , Pirazóis/síntese química , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacologia , Relação Estrutura-Atividade , Tienopiridinas/síntese química , Tienopiridinas/química , Tienopiridinas/metabolismo , Tienopiridinas/farmacologiaRESUMO
Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.
Assuntos
Janus Quinase 2/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Tienopiridinas/síntese química , Animais , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Cristalografia por Raios X , Humanos , Janus Quinase 1/química , Janus Quinase 2/química , Leucócitos Mononucleares/efeitos dos fármacos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Suínos , Tienopiridinas/química , Tienopiridinas/farmacologiaRESUMO
Thienopyridines (ticlopidine, clopidogrel, and prasugrel) require in vivo metabolism to exhibit a critical thiol group in the active form that binds to the P2Y12 platelet receptor to inhibit platelet activation. We hypothesized that formation of thienopyridine-derived nitrosothiols (ticlopidine-SNO, clopidogrel-SNO, and prasugrel-SNO) occurs directly from the respective parent drug. Pharmaceutical-grade thienopyridine (ticlopidine, clopidogrel chloride, clopidogrel sulfate, clopidogrel besylate, or prasugrel) was added to nitrite in aqueous solution to form the respective thienopyridine-SNO (Th-SNO). An isolated aortic ring preparation was used to test vasoactivity of the Th-SNO derivatives. Increasing nitrite availability resulted in increased Th-SNO formation for all drugs (other than ticlopidine). Th-SNO induced significant endothelium-independent relaxation of preconstricted aortic rings. Clopidogrel-chloride-SNO displayed rapid-release kinetics in a chemical environment, which was reflected by immediate and transient vasorelaxation when compared with the SNO derivatives of the other thienopyridines. Accounting for differences in yield, clopidogrel-chloride-SNO exhibited the greatest propensity to immediately relax vascular tissue. Th-SNO derivatives exhibit nitrovasodilator properties by supplying NO that can directly activate vascular soluble guanylate cyclase to induce vasorelaxation. Differences in SNO yield and vasoactivity exist between thienopyridine preparations that might be important to our understanding of the direct pharmacological effectiveness of thienopyridines on vascular and platelet function.
Assuntos
S-Nitrosotióis/farmacologia , Tienopiridinas/farmacologia , Vasodilatadores/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Clopidogrel , Glutationa/análogos & derivados , Glutationa/farmacologia , Guanilato Ciclase/antagonistas & inibidores , Concentração de Íons de Hidrogênio , Técnicas In Vitro , Medições Luminescentes , Masculino , Espectrometria de Massas , Estrutura Molecular , Nitrocompostos/farmacologia , Oxidiazóis/farmacologia , Ozônio/química , Piperazinas/química , Piperazinas/farmacologia , Cloridrato de Prasugrel , Quinoxalinas/farmacologia , Coelhos , S-Nitrosotióis/análise , S-Nitrosotióis/química , Nitrito de Sódio/química , Nitrito de Sódio/farmacologia , Espectrofotometria Ultravioleta , Tienopiridinas/química , Tiofenos/química , Tiofenos/farmacologia , Ticlopidina/análogos & derivados , Ticlopidina/química , Ticlopidina/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/químicaRESUMO
To explore novel ADP receptor inhibitors with anti-thrombotic activity, eighteen compounds were synthesized and their structures were confirmed by 1H NMR and MS. The results showed that the activity of compound C1 was superior to ticlopidine in platelet aggregation inhibition tests in vivo and worthy for further investigation. Compounds A4, B2, C4 and C7 possessed moderate platelet aggregation inhibitory activities.
Assuntos
Inibidores da Agregação Plaquetária/síntese química , Inibidores da Agregação Plaquetária/farmacologia , Agregação Plaquetária/efeitos dos fármacos , Tienopiridinas/síntese química , Tienopiridinas/farmacologia , Animais , Masculino , Estrutura Molecular , Inibidores da Agregação Plaquetária/química , Antagonistas do Receptor Purinérgico P2Y/síntese química , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Distribuição Aleatória , Ratos , Ratos Wistar , Tienopiridinas/químicaRESUMO
A novel series of CHK1 inhibitors based on thienopyridine template has been designed and synthesized. These inhibitors maintain critical hydrogen bonding with the hinge and conserved water in the ATP binding site. Several compounds show single digit nanomolar CHK1 activities. Compound 70 shows excellent enzymatic activity of 1 nM.