An efficient method is described for the solid-supported synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine. The key pyridine building block was reacted with polymer-supported amines, followed by replacement of the second chlorine with amines, nitro group reduction, and imidazole ring closure with aldehydes. Depending on the combination of polymer-supported and solution-phase reagents, the strategy allowed for the simple preparation of the target trisubstituted derivatives with variable positioning of the pyridine nitrogen atom. Additionally, after a slight modification of the method, the preparation of strictly isomeric imidazopyridines was possible.

• MeSH
• aldehydy chemie   MeSH
• imidazoly chemická syntéza   MeSH
• indikátory a reagencie MeSH
• isomerie MeSH
• pyridiny chemická syntéza   MeSH
• techniky syntézy na pevné fázi * MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Herein, we report an efficient synthetic approach towards trisubstituted imidazo [4,5-c]pyridines designed as inhibitors of Bruton's tyrosine kinase (BTK). Two alternative synthetic routes for the simple preparation of desired compounds with variable substitutions at the N1, C4, C6 positions were introduced with readily available building blocks. Further, the developed synthetic approach was feasible for isomeric compounds bearing imidazo [4,5-b]pyridine scaffolds. In contrast to expectations based on previous studies, the imidazo [4,5-c]pyridine inhibitor exhibited a significantly higher activity against BTK compared to its imidazo [4,5-b]pyridine isomer. An inherent SAR study in the series of imidazo [4,5-c]pyridine compounds revealed a remarkably high tolerance of C6 substitutions for both hydrophobic and hydrophilic substituents. Preliminary cellular experiments indicated selective BTK targeting in Burkitt lymphoma and mantle cell lymphoma cell lines. The inhibitors could thus serve as starting points for further development, eventually leading to BTK inhibitors that could be used after ibrutinib failure.

• MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nehodgkinský lymfom farmakoterapie   MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• pyridiny farmakologie   terapeutické užití   MeSH
• signální transdukce MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

This article provides an overview of compounds based on imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[4,5-b]pyridine and imidazo[4,5-c]pyridine scaffolds, which act as potent ligands of diverse molecular targets localized in the central nervous system. A literature survey revealed that various imidazopyridines can be powerful modulators of several diseases associated with CNS dysfunction including Alzheimer's disease, Parkinson's disease, schizophrenia, depression or sleeping disorders. A description of target enzymes (e.g., β-secretase, γ-secretase, fatty acid amide hydrolase - FAAH, leucine-rich repeat kinase 2 - LRRK2) and selected receptors (e.g., GABA-A, histamine H3, serotonin 5-HT3, 5-HT4, 5-HT6, dopamine D4, adenosine A2A, orexin), modes of action of imidazopyridine-based ligands and their therapeutic importance is discussed.

• MeSH
• cílená molekulární terapie MeSH
• duševní poruchy farmakoterapie   MeSH
• imidazoly chemie   farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• ligandy MeSH
• neurodegenerativní nemoci farmakoterapie   MeSH
• pyridiny chemie   farmakologie   terapeutické užití   MeSH
• racionální návrh léčiv * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Spleen tyrosine kinase (SYK) and Bruton's tyrosine kinase (BTK) are attractive targets in human haematological malignancies with excessively activated B-cell receptor (BCR) signalling pathways. Entospletinib is a SYK inhibitor that has been evaluated as a clinical candidate. We designed and prepared five isosteres in which the imidazo[1,2-a]pyrazine scaffold of entospletinib was altered to pyrazolo[3,4-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, imidazo[4,5-b]pyridine, imidazo[4,5-c]pyridine and purine. The last two isosteres were the most potent SYK inhibitors, with IC50 values in the mid-nanomolar range. Importantly, three compounds also inhibited BTK more effectively than did entospletinib. Further experiments then showed that BCR signalling was suppressed in Ramos cells by the potent compounds. Preliminary kinase inhibition screening also revealed LCK and SRC as additional targets. Our results further support the hypothesis that multikinase targeting compounds could produce more robust responses in the treatment of B lymphoid neoplasms.

• MeSH
• fosforylace MeSH
• indazoly aplikace a dávkování   farmakologie   MeSH
• inhibitory proteinkinas aplikace a dávkování   farmakologie   MeSH
• kinasa Syk antagonisté a inhibitory   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protoonkogenní proteiny c-bcr metabolismus   MeSH
• pyraziny aplikace a dávkování   farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6receptor partial inverse agonist in Gssignaling (Ki = 6 nM, IC50 = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT6R-elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest.

• MeSH
• HEK293 buňky MeSH
• imidazoly chemická syntéza   chemie   farmakologie   MeSH
• kognice účinky léků   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• molekulární struktura MeSH
• potkani Sprague-Dawley MeSH
• potkani Wistar MeSH
• pyridiny chemická syntéza   chemie   farmakologie   MeSH
• receptory serotoninové metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A novel group of 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinolines was prepared via a microwave assisted one-pot telescopic approach. The synthetic sequence involves the formation of an amine precursor of imidazo [1,2-a]pyridine via condensation and reduction under microwave irradiation. Subsequently, the Pictet-Spengler cyclisation reaction occurs with ketones (cyclic or acyclic) to obtain substituted 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinolines in excellent yields. The compounds were tested as neuroprotective agents. Observed protection of neuron-like cells, SH-SY5Y differentiated with ATRA, in Parkinson's and Huntington's disease models inspired further mechanistic studies of protective activity against damage induced by 1-methyl-4-phenylpyridinium (MPP+), a compound causing Parkinson's disease. The novel compounds exhibit similar or higher potency than ebselen, an established drug with antioxidant activity, in the cells against MPP + -induced total cellular superoxide production and cell death. However, they exhibit a significantly higher capacity to reduce mitochondrial superoxide and preserve mitochondrial membrane potential. We also observed marked differences between a selected derivative and ebselen in terms of normalizing MPP + -induced phosphorylation of Akt and ERK1/2. The cytoprotective activity was abrogated when signaling through cannabinoid receptor CB2 was blocked. The compounds also inhibit both acetylcholine and butyrylcholine esterases. Overall the data show that novel 5,6-dihydropyrido [2',1':2,3]imidazo [4,5-c]quinoline have a broad cytoprotective activity which is mediated by several mechanisms including mitoprotection.

• MeSH
• chinoliny * farmakologie   chemie   chemická syntéza   MeSH
• cholinesterasové inhibitory * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• neuroprotektivní látky * farmakologie   chemie   chemická syntéza   MeSH
• receptor kanabinoidní CB2 * metabolismus   antagonisté a inhibitory   MeSH
• signální transdukce * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The B-cell receptor (BCR) signalling pathway is tightly connected with the function, proliferation and survival of B cells. Aberrant BCR signalling, typical for various B cell malignancies, has been successfully targeted by small molecules kinase inhibitors that have shown an encouraging effect in clinical settings. On the other hand, adverse effects limiting the clinical use of these agents stimulate further discovery and development of drug against the BCR signalosome. This project is focused on development of novel kinase inhibitors of the BCR signalosome members: BTK (Brutton tyrosine kinase), SYK (spleen tyrosine kinase) and PI3K (phosphatidylinositol 3-kinases). We have already designed and prepared several imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines, exploited only rarely as kinase inhibitors. Within this project, the compounds will be further optimized and studied to clarify their structure-activity relationships in biochemical and cellular assays. Therapeutic efficacy of selected lead will be determined in a suitable mouse model of B-cell lymphoma.

Signalizace B-buněčného receptoru (BCR) se podílí na funkci, proliferaci a přežívání B lymfocytů. Aberantní signalizace BCR, která je typická pro různé B-buněčné malignity, je považována za racionální a poměrně efektivní cíl nízkomolekulárních sloučenin, které již prokázaly svou terapeutickou účinnost v klinických experimentech. Na druhou stranu však jejich použití omezují některé nežádoucí účinky, což nadále stimuluje k vývoji dalších inhibitorů BCR signalosomu. Tento projekt je zaměřen na vývoj nových inhibitorů kinas právě v rámci BCR signalosomu, a to konkrétně na BTK (Bruttonova tyrosinová kinasa), SYK (slezinová tyrosinová kinasa) a PI3K (fosfatidylinositol 3-kinasy). Nedávno se nám podařilo navrhnout a připravit několik imidazo[4,5-b]pyridinů a imidazo[4,5-c]pyridinů, které jako inhibitory kinas nebyly dosud využívány. V rámci tohoto projektu hodláme optimalizovat tyto sloučeniny a objasňovat vztahy mezi strukturou a aktivitou v biochemických a buněčných experimentech.Terapeutická účinnost aktivních derivátů bude případně ověřena v myším modelu vhodného B lymfomu.

• MeSH
• B-buněčný lymfom farmakoterapie   MeSH
• inhibitory fosfoinositid-3-kinasy terapeutické užití   MeSH
• inhibitory tyrosinkinasy antagonisté a inhibitory   MeSH
• kinasa Syk antagonisté a inhibitory   MeSH
• lidé MeSH
• proteinkinasa BTK antagonisté a inhibitory   MeSH
• protinádorové látky terapeutické užití   MeSH
• signální transdukce MeSH
• vyvíjení léků MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• hodnotící studie MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• onkologie
• farmacie a farmakologie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

A series of 3-deazapurine ribonucleosides 5a-5l bearing diverse C-substituents (alkyl, aryl and heteroaryl) in the position 6 were prepared by Pd-catalyzed cross-coupling reactions of either free 6-chloro-3-deazapurine ribonucleoside 4 or its acetyl protected congener 3 followed by deprotection. An improved synthesis of the starting 4-chloro-1-(2,3,5-tri-O-acetyl-ß-D-ribofuranosyl)-1H-imidazo[4,5-c]pyridine (3) was developed by the application of Vorbrüggen glycosylation of silylated nucleobase with 1,2,3,5-tetra-O-acetyl-ß-D-ribofuranose (2). None of compounds 5a-5l showed any considerable cytostatic or antiviral activity.

• MeSH
• financování organizované MeSH
• protinádorové látky chemická syntéza   MeSH
• puriny farmakokinetika   chemická syntéza   MeSH
• ribonukleosidy farmakokinetika   fyziologie   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH

• MeSH
• antibakteriální látky farmakokinetika   škodlivé účinky   terapeutické užití   MeSH
• Clostridioides difficile patogenita   účinky léků   MeSH
• fekální transplantace MeSH
• fidaxomicin aplikace a dávkování   terapeutické užití   MeSH
• klostridiové infekce * etiologie   farmakoterapie   chemicky indukované   MeSH
• lidé MeSH
• metronidazol aplikace a dávkování   terapeutické užití   MeSH
• rifaximin terapeutické užití   MeSH
• tigecyklin aplikace a dávkování   terapeutické užití   MeSH
• vankomycin aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

• MeSH
• antibakteriální látky škodlivé účinky   MeSH
• Clostridioides difficile patogenita   růst a vývoj   MeSH
• fekální transplantace MeSH
• fidaxomicin terapeutické užití   MeSH
• klostridiové infekce * diagnóza   přenos   terapie   MeSH
• lidé MeSH
• metronidazol aplikace a dávkování   terapeutické užití   MeSH
• pseudomembranózní enterokolitida * patofyziologie   přenos   MeSH
• rifaximin terapeutické užití   MeSH
• střevní mikroflóra účinky léků   MeSH
• tigecyklin aplikace a dávkování   terapeutické užití   MeSH
• vankomycin aplikace a dávkování   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH