RESUMO
TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader-Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC50 ≈ 30 µM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.
Assuntos
Simulação de Acoplamento Molecular , Bloqueadores dos Canais de Potássio , Canais de Potássio de Domínios Poros em Tandem , Piridinas , Humanos , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Canais de Potássio de Domínios Poros em Tandem/química , Piridinas/síntese química , Piridinas/químicaRESUMO
The two-pore potassium channel TASK-3 has been shown to localize to both the plasma membrane and the mitochondrial inner membrane. TASK-3 is highly expressed in melanoma and breast cancer cells and has been proposed to promote tumor formation. Here we investigated whether pharmacological modulation of TASK-3, and specifically of mitochondrial TASK-3 (mitoTASK-3), had any effect on cancer cell survival and mitochondrial physiology. A novel, mitochondriotropic version of the specific TASK-3 inhibitor IN-THPP has been synthesized by addition of a positively charged triphenylphosphonium moiety. While IN-THPP was unable to induce apoptosis, mitoIN-THPP decreased survival of breast cancer cells and efficiently killed melanoma lines, which we show to express mitoTASK-3. Cell death was accompanied by mitochondrial membrane depolarization and fragmentation of the mitochondrial network, suggesting a role of the channel in the maintenance of the correct function of this organelle. In accordance, cells treated with mitoIN-THPP became rapidly depleted of mitochondrial ATP which resulted in activation of the AMP-dependent kinase AMPK. Importantly, cell survival was not affected in mouse embryonic fibroblasts and the effect of mitoIN-THPP was less pronounced in human melanoma cells stably knocked down for TASK-3 expression, indicating a certain degree of selectivity of the drug both for pathological cells and for the channel. In addition, mitoIN-THPP inhibited cancer cell migration to a higher extent than IN-THPP in two melanoma cell lines. In summary, our results point to the importance of mitoTASK-3 for melanoma cell survival and migration.
Assuntos
Mitocôndrias/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Pirimidinas/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/fisiologia , Bloqueadores dos Canais de Potássio/síntese química , Pirimidinas/síntese química , Espécies Reativas de Oxigênio/metabolismoRESUMO
The ATP-synthase inhibitor bedaquiline is effective against drug-resistant tuberculosis but is extremely lipophilic (clogP 7.25) with a very long plasma half-life. Additionally, inhibition of potassium current through the cardiac hERG channel by bedaquiline, is associated with prolongation of the QT interval, necessitating cardiovascular monitoring. Analogues were prepared where the naphthalene C-unit was replaced with substituted pyridines to produce compounds with reduced lipophilicity, anticipating a reduction in half-life. While there was a direct correlation between in vitro inhibitory activity against M. tuberculosis (MIC90) and compound lipophilicity, potency only fell off sharply below a clogP of about 4.0, providing a useful lower bound for analogue design. The bulk of the compounds remained potent inhibitors of the hERG potassium channel, with notable exceptions where IC50 values were at least 5-fold higher than that of bedaquiline. Many of the compounds had desirably higher rates of clearance than bedaquiline, but this was associated with lower plasma exposures in mice, and similar or higher MICs resulted in lower AUC/MIC ratios than bedaquiline for most compounds. The two compounds with lower potency against hERG exhibited similar clearance to bedaquiline and excellent efficacy in vivo, suggesting further exploration of C-ring pyridyls is worthwhile.
Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Piridinas/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Diarilquinolinas/síntese química , Diarilquinolinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
Assuntos
Antituberculosos/farmacologia , Diarilquinolinas/farmacologia , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Piridinas/farmacologia , Antituberculosos/síntese química , Antituberculosos/química , Diarilquinolinas/síntese química , Diarilquinolinas/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
Novel bacterial type II topoisomerase inhibitors (NBTIs) constitute a promising new class of antibacterial agents. We report a series of NBTIs with potent anti-staphylococcal activity and diminished hERG inhibition. Dioxane-linked compound 9 demonstrated MICs ≤1⯵g/mL against both methicillin-susceptible (MSSA) and -resistant Staphylococcus aureus (MRSA), accompanied by reduced hERG inhibition as compared to cyclohexane- or piperidine-linked analogs.
Assuntos
Antibacterianos/farmacologia , DNA Topoisomerases Tipo II/metabolismo , Dioxanos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Quinolinas/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Cristalografia por Raios X , Dioxanos/química , Relação Dose-Resposta a Droga , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/químicaRESUMO
Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC50 values of 1.8 and 1.9â µg mL-1 against T.â cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead.
Assuntos
Antiprotozoários/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Triazóis/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/toxicidade , Linhagem Celular Tumoral , Inibidores das Enzimas do Citocromo P-450/síntese química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Inibidores das Enzimas do Citocromo P-450/toxicidade , Canal de Potássio ERG1/metabolismo , Humanos , Leishmania/efeitos dos fármacos , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Ratos , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/toxicidade , Triazóis/síntese química , Triazóis/química , Triazóis/toxicidade , Trypanosoma/efeitos dos fármacosRESUMO
The potassium channel Kv1.3 is highly expressed in the mitochondria of various cancerous cells. Here we show that direct inhibition of Kv1.3 using two mitochondria-targeted inhibitors alters mitochondrial function and leads to reactive oxygen species (ROS)-mediated death of even chemoresistant cells independently of p53 status. These inhibitors killed 98% of ex vivo primary chronic B-lymphocytic leukemia tumor cells while sparing healthy B cells. In orthotopic mouse models of melanoma and pancreatic ductal adenocarcinoma, the compounds reduced tumor size by more than 90% and 60%, respectively, while sparing immune and cardiac functions. Our work provides direct evidence that specific pharmacological targeting of a mitochondrial potassium channel can lead to ROS-mediated selective apoptosis of cancer cells in vivo, without causing significant side effects.
Assuntos
Antineoplásicos/farmacologia , Canal de Potássio Kv1.3/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Bloqueadores dos Canais de Potássio/farmacologia , Idoso , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Cumarínicos/farmacologia , Estabilidade de Medicamentos , Feminino , Humanos , Canal de Potássio Kv1.3/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Terapia de Alvo Molecular , Compostos Organofosforados/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/químicaRESUMO
The SK3 potassium channel is involved in the development of bone metastasis and in the settlement of cancer cells in Ca(2+) -rich environments. Ohmline, which is a lactose-based glycero-ether lipid, is a lead compound that decreases SK3 channel activity and consequently limits the migration of SK3-expressing cells. Herein we report the synthesis of three new ohmline analogues in which the connection of the disaccharide moieties (1â6 versus 1â4) and the stereochemistry of the glycosyl linkage was studied. Compound 2 [3-(hexadecyloxy)-2-methoxypropyl-6-O-α-d-glucopyranosyl-ß-d-galactopyranoside], which possesses an α-glucopyranosyl-(1â6)-ß-galactopyranosyl moiety, was found to decrease SK3 current amplitude (70 % inhibition at 10â µm), displace SK3 protein outside caveolae, and decrease constitutive Ca(2+) entry (50 % inhibition at 300â nm) and SK3-dependent cell migration (30 % at 300â nm) at a level close to that of the benchmark compound ohmline. Compound 2, which decreases the activity of SK3 channel (but not SK2 channel), is a new drug candidate to reduce cancer cell migration and to prevent bone metastasis.
Assuntos
Dissacarídeos/farmacologia , Glicolipídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Cavéolas/efeitos dos fármacos , Cavéolas/metabolismo , Movimento Celular/efeitos dos fármacos , Dissacarídeos/síntese química , Glicolipídeos/síntese química , Células HEK293 , Humanos , Potenciais da Membrana/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/síntese química , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Estereoisomerismo , Compostos de Trimetilsilil/químicaRESUMO
A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
Assuntos
Azetidinas/síntese química , Azetidinas/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Peso Corporal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Feminino , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Relação Estrutura-AtividadeRESUMO
Four analogs of HelaTx1, a 25-mer peptide from scorpion venom, were synthesized by deleting its C-terminal hexapeptide fragment and N-terminal Ser residue and by inserting an amino acid in the middle part of the molecule. CD spectrum of HelaTx1(1-19) was almost superimposable to that of native HelaTx1. Functional characterization showed that HelaTx1(1-19) retained its inhibitory activity on Kv1.1 channel although 3 times less potent than HelaTx1, indicating that C-terminal part of HelaTx1 was not essential for its conformation and activity. Further deletion of N-terminal Ser residue and insertion of Ala in the middle part of the molecule affected the CD spectra and resulted in the decrease of activity.
Assuntos
Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/metabolismo , Venenos de Escorpião/química , Escorpiões/química , Sequência de Aminoácidos , Animais , Fenômenos Eletrofisiológicos , Oócitos/metabolismo , Peptídeos/síntese química , Bloqueadores dos Canais de Potássio/síntese química , Relação Estrutura-Atividade , XenopusRESUMO
We synthesized and evaluated a series of compounds for their allosteric modulation at the Kv11.1 (hERG) channel. Most compounds were negative allosteric modulators of [(3)H]dofetilide binding to the channel, in particular 7f, 7h-j and 7p. Compounds 7f and 7p were the most potent negative allosteric modulators amongst all ligands, significantly increasing the dissociation rate of dofetilide in the radioligand kinetic binding assay, while remarkably reducing the affinities of dofetilide and astemizole in a competitive displacement assay. Additionally, both 7f and 7p displayed peculiar displacement characteristics with Hill coefficients significantly distinct from unity as shown by e.g., dofetilide, further indicative of their allosteric effects on dofetilide binding. Our findings in this investigation yielded several promising negative allosteric modulators for future functional and clinical research with respect to their antiarrhythmic propensities, either alone or in combination with known Kv11.1 blockers.
Assuntos
Acetamidas/farmacologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Naftiridinas/síntese química , Naftiridinas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Regulação Alostérica/efeitos dos fármacos , Arritmias Cardíacas/tratamento farmacológico , Células Cultivadas , Relação Dose-Resposta a Droga , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/química , Células HEK293 , Humanos , Cinética , Estrutura Molecular , Naftiridinas/química , Fenetilaminas/química , Fenetilaminas/metabolismo , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Piridinas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
The present study describes the optimization of a series of novel benzoxazole-piperidine (piperazine) derivatives combining high dopamine D2 and serotonin 5-HT1A, 5-HT2A receptor affinities. Of these derivatives, the pharmacological features of compound 29 exhibited high affinities for the DA D2, 5-HT1A and 5-HT2A receptors, but low affinities for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. Furthermore, compound 29 reduced apomorphine-induced climbing and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head twitching without observable catalepsy, even at the highest dose tested. Thus, compound 29 is a promising candidate as a multi-target antipsychotic treatment.
Assuntos
Antipsicóticos/síntese química , Oxazóis/síntese química , Piperazinas/síntese química , Piperidinas/síntese química , Esquizofrenia/tratamento farmacológico , Animais , Antipsicóticos/farmacologia , Antipsicóticos/toxicidade , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Camundongos , Oxazóis/farmacologia , Oxazóis/toxicidade , Técnicas de Patch-Clamp , Piperazinas/farmacologia , Piperazinas/toxicidade , Piperidinas/farmacologia , Piperidinas/toxicidade , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , Ratos , Receptores de Dopamina D2/agonistas , Agonistas do Receptor 5-HT1 de Serotonina/síntese química , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/toxicidade , Agonistas do Receptor 5-HT2 de Serotonina/síntese química , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/toxicidade , Relação Estrutura-Atividade , SuínosRESUMO
A series of novel teraryl oxazolidinone compounds was designed, synthesized, and evaluated for their antimicrobial activity and toxicities. The compounds with aromatic N-heterocyclic substituents at the 4-position of pyrazolyl ring showed better antibacterial activity against the tested bacteria than other compounds with different patterns of substitution. Among all potent compounds, 10f exhibited promising safety profile in MTT assays and in hERG K(+) channel inhibition test. Furthermore, its phosphate was found to be highly soluble in water (47.1 mg/mL), which is beneficial for the subsequent in vivo test. In MRSA systemic infection mice models, 10f phosphate exerted significantly improved survival protection compared with linezolid. The compound also demonstrated high oral bioavailability (F = 99.1%). Moreover, from the results of in vivo toxicology experiments, 10f phosphate would be predicted to have less bone marrow suppression.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Animais , Anti-Infecciosos/toxicidade , Bactérias/efeitos dos fármacos , Disponibilidade Biológica , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Linezolida , Staphylococcus aureus Resistente à Meticilina , Camundongos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Oxazóis/farmacocinética , Oxazolidinonas/farmacocinética , Oxazolidinonas/uso terapêutico , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Relação Estrutura-Atividade , Sais de Tetrazólio , TiazóisRESUMO
Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11 g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development.
Assuntos
Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Depressores do Apetite/farmacologia , Peso Corporal/efeitos dos fármacos , Ciclobutanos/farmacologia , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Hepatócitos/metabolismo , Ensaios de Triagem em Larga Escala , Humanos , Técnicas In Vitro , Lipidoses/tratamento farmacológico , Microssomos Hepáticos/metabolismo , Fosfolipídeos/metabolismo , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Despite recent success there remains a high therapeutic need for the development of drugs targeting diseases associated with the metabolic syndrome. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, a series of 3,6-disubstituted pyridazines was evaluated. During optimization several issues of the initial lead structures had to be resolved, such as selectivity over related GPCRs, inhibition of the hERG channel as well as the potential to induce phospholipidosis. Utilizing property-based design, we could demonstrate that all parameters can significantly be improved by consequently increasing the polarity of the compounds. By this strategy, we succeeded in identifying potent and orally available MCH-R1 antagonists with good selectivity over M1 and 5-HT2A and an improved safety profile with respect to hERG inhibition and phospholipidosis.
Assuntos
Fármacos Antiobesidade/síntese química , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Lipidoses/tratamento farmacológico , Fosfolipídeos/metabolismo , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacologia , Bloqueadores dos Canais de Potássio/farmacocinética , Piridazinas/farmacocinética , Ratos , Ratos Wistar , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators. To overcome this limitation, in the present work, a ligand-based virtual screening was performed using as separate search queries two conformations of NS1643, the most deeply investigated and better characterized hERG activator. The library of compounds resulting from the virtual screening was then clustered based on recurring chemical features, and 5 hits were selected to be evaluated for their ability to enhance hERG current in vitro. Compound 3 showed a good activating effect, also displaying a mechanism of action similar to that of NS1643. Moreover, the most interesting compounds were further investigated by synthesizing in a parallel fashion some analogs, with the aim to get insights about structure-activity relationships.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Bloqueadores dos Canais de Potássio/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/química , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Ligantes , Estrutura Molecular , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
Cardiac arrhythmia is a major cause of death in the world. Among many delayed rectifier potassium currents, the rapid delayed rectifier K current (IKr) plays an important role in the repolarization of cardiac tissue. The inhibition of IKr can delay repolarization and lead to an increase in the QT interval of the electrocardiogram, which is the treatment mechanism of Class III antiarrhythmic agents. Therefore, IKr can be considered as the drug target for the treatment of cardiac arrhythmia. In the current study, a series of 4-chromanone compounds (WR1-WR12) were well designed and synthesized as IKr inhibitors. The results disclosed that two compounds displayed potent inhibitory activities against IKr. Moreover, our structure-activity relationship results might provide necessary information for the rational design of inhibitors for IKr.
Assuntos
Antiarrítmicos/síntese química , Antiarrítmicos/farmacologia , Cromonas/síntese química , Cromonas/farmacologia , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Potenciais de Ação , Antiarrítmicos/metabolismo , Ligação Competitiva , Cromonas/metabolismo , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Estrutura Molecular , Bloqueadores dos Canais de Potássio/metabolismo , Relação Estrutura-AtividadeRESUMO
Insulin secretion by pancreatic ß-cells in response to glucose or other secretagogues is tightly coupled to membrane potential. Various studies have highlighted the prospect of enhancing insulin secretion in a glucose-dependent manner by blocking voltage-gated potassium channels (K(v)) and calcium-activated potassium channels (K(Ca)). Such strategy is expected to present a lower risk for hypoglycemic events compared to KATP channel blockers. Our group recently reported the discovery of a new insulinotropic agent, cardiotoxin-I (CTX-I), from the Naja kaouthia snake venom. In the present study, we report the design and synthesis of [Lys(52)]CTX-I(41-60) via structure-guided modification, a truncated, equipotent analogue of CTX-I, and demonstrate, using various pharmacological inhibitors, that this derivative probably exerts its action through Kv channels. This new analogue could represent a useful pharmacological tool to study ß-cell physiology or even open a new therapeutic avenue for the treatment of type 2 diabetes.
Assuntos
Proteínas Cardiotóxicas de Elapídeos/síntese química , Proteínas Cardiotóxicas de Elapídeos/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Insulina/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Venenos Elapídicos/química , Glucose/farmacologia , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Modelos Moleculares , Conformação Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Cálcio-Ativados/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/efeitos dos fármacos , Ratos , Rubídio/metabolismo , Radioisótopos de Rubídio , Estimulação QuímicaRESUMO
Combined blockade of IKr and IKs potassium channels is considered to be a promising therapeutic strategy for arrhythmia. In this study, we designed and synthesized 15 derivatives through modifying the hit compound 7 that was discovered by screening in-house database by whole-patch clamp technique. All of the compounds were evaluated on CHO and HEK 293 cell lines stably expressing hERG (IKr) and hKCNQ1/KCNE1 (IKs) potassium channels, and half of them exhibited improved dual IKr and IKs inhibitory effects compared to the hit compound. Compounds 7a and 7b with potent dual inhibitory activities were selected for further in vivo evaluations. Due to the preferable pharmacological behaviors, compound 7a deserved further optimization as a promising lead compound.
Assuntos
Arritmias Cardíacas/tratamento farmacológico , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Piperazinas/química , Piperazinas/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Animais , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologia , Células CHO , Cricetinae , Cricetulus , Eletrocardiografia/efeitos dos fármacos , Cobaias , Células HEK293 , Humanos , Ouabaína/efeitos adversos , Piperazina , Piperazinas/síntese química , Piperazinas/uso terapêutico , Bloqueadores dos Canais de Potássio/síntese química , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/uso terapêuticoRESUMO
A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.