RESUMO
In this study, we present the discovery and pharmacological characterization of a new series of 6-piperazinyl-7-azaindoles. These compounds demonstrate potent antagonism and selectivity against the 5-HT6 receptor. Our research primarily focuses on optimizing the lead structure and investigating the structure-activity relationship (SAR) of these compounds. Our main objective is to improve their activity and selectivity against off-target receptors. Overall, our findings contribute to the advancement of novel compounds targeting the 5-HT6 receptor. Compound 29 exhibits significant promise in terms of pharmacological, physicochemical, and ADME (Absorption, Distribution, Metabolism, and Excretion) properties. Consequently, it merits thorough exploration as a potential drug candidate due to its favorable activity profile and successful outcomes in a range of in vivo experiments.
Assuntos
Piridinas , Antagonistas da Serotonina , Piridinas/química , Antagonistas da Serotonina/química , Relação Estrutura-AtividadeRESUMO
The mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (MNKs 1/2) and their downstream target eIF4E, play a role in oncogenic transformation, progression and metastasis. These results provided rationale for development of first MNKs inhibitors, currently in clinical trials for cancer treatment. Inhibitors of the MNKs/eIF4E pathway are also proposed as treatment strategy for inflammatory conditions. Here we present results of optimization of indazole-pyridinone derived MNK1/2 inhibitors among which compounds 24 and 26, selective and metabolically stable derivatives. Both compounds decreased levels of eIF4E Ser206 phosphorylation (pSer209-eIF4E) in MOLM16 cell line. When administered in mice compounds 24 and 26 significantly improved survival rates of animals in the endotoxin lethal dose challenge model, with concomitant reduction of proinflammatory cytokine levels - TNFα and IL-6 in serum. Identified MNK1/2 inhibitors represent a novel class of immunomodulatory compounds with a potential for the treatment of inflammatory diseases including sepsis.
Assuntos
Fatores Imunológicos/síntese química , Indazóis/química , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridonas/química , Choque Séptico/tratamento farmacológico , Sequência de Aminoácidos , Animais , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Descoberta de Drogas , Endotoxinas/metabolismo , Fator de Iniciação 4E em Eucariotos/metabolismo , Humanos , Fatores Imunológicos/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Choque Séptico/induzido quimicamente , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer's disease, Parkinson's disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (aka CRID3 or MCC 950) as our starting point and undertook a Structure-Activity Relationship (SAR) analysis and subsequent scaffold-hopping exercise. This resulted in the rational design of a series of novel ester-substituted urea compounds that are highly potent and selective NLRP3 inflammasome inhibitors, as exemplified by compounds 44 and 45. It is hypothesized that the ester moiety acts as a highly permeable delivery vehicle and is subsequently hydrolyzed to the carboxylic acid active species by carboxylesterase enzymes. These molecules are greatly differentiated from the state-of-the-art and offer potential in the treatment of NLRP3-driven diseases, particularly where tissue penetration is required.
Assuntos
Ésteres/farmacologia , Indenos/farmacologia , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/farmacologia , Animais , Sangue/metabolismo , Desenho de Fármacos , Estabilidade de Medicamentos , Ésteres/síntese química , Ésteres/metabolismo , Furanos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Indenos/síntese química , Indenos/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas , Sulfonas/química , Células THP-1RESUMO
In oncology, the "Warburg effect" describes the elevated production of energy by glycolysis in cancer cells. The ubiquitous and hypoxia-induced 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) plays a noteworthy role in the regulation of glycolysis by producing fructose-2,6-biphosphate (F-2,6-BP), a potent activator of the glycolysis rate-limiting phosphofructokinase PFK-1. Series of amides and sulfonamides derivatives based on a N-aryl 6-aminoquinoxaline scaffold were synthesized and tested for their inhibition of PFKFB3 in vitro in a biochemical assay as well as in HCT116 cells. The carboxamide series displayed satisfactory kinetic solubility and metabolic stability, and within this class, potent lead compounds with low nanomolar activity have been identified with a suitable profile for further in vivo evaluation.
Assuntos
Amidas/química , Fosfofrutoquinase-2/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Sulfonamidas/química , Células HCT116 , Humanos , Cinética , SolubilidadeRESUMO
Maternal embryonic leucine zipper kinase (MELK) is involved in several key cellular processes and displays increased levels of expression in numerous cancer classes (colon, breast, brain, ovary, prostate and lung). Although no selective MELK inhibitors have yet been approved, increasing evidence suggest that inhibition of MELK would constitute a promising approach for cancer therapy. A weak high-throughput screening hit (17, IC50â¯≈â¯5⯵M) with lead-like properties was optimized for MELK inhibition. The early identification of a plausible binding mode by molecular modeling offered guidance in the choice of modifications towards compound 52 which displayed a 98â¯nM IC50. A good selectivity profile was achieved for a representative member of the series (29) in a 486 protein kinase panel. Future elaboration of 52 has the potential to deliver compounds for further development with chemotherapeutic aims.
Assuntos
Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Tiofenos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50RESUMO
Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK-2 plays a significant role by producing fructose-2,6-biphosphate; the most potent activator of the glycolysis rate-limiting step performed by phosphofructokinase PFK-1. Herein, the synthesis, biological evaluation and structure-activity relationship of novel inhibitors of 6-phosphofructo-2-kinase/fructose-2,6-biphosphataseâ 3 (PFKFB3), which is the ubiquitous and hypoxia-induced isoform of PFK-2, are reported. X-ray crystallography and docking were instrumental in the design and optimisation of a series of N-aryl 6-aminoquinoxalines. The most potent representative, N-(4-methanesulfonylpyridin-3-yl)-8-(3-methyl-1-benzothiophen-5-yl)quinoxalin-6-amine, displayed an IC50 of 14â nm for the target and an IC50 of 0.49â µm for fructose-2,6-biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncology.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fosfofrutoquinase-2/antagonistas & inibidores , Quinoxalinas/química , Quinoxalinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Células HCT116 , Humanos , Ácido Láctico/antagonistas & inibidores , Ácido Láctico/biossíntese , Modelos Moleculares , Estrutura Molecular , Fosfofrutoquinase-2/metabolismo , Quinoxalinas/síntese química , Relação Estrutura-AtividadeRESUMO
MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, ß-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals. There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.
Assuntos
Antineoplásicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/química , Transdução de SinaisRESUMO
A series of 1-Sulfonyl-6-Piperazinyl-7-Azaindoles, showing strong antagonistic activity to 5-HT6 receptor (5-HT6R) was synthesized and characterized. The series was optimized to reduce activity on D2 receptor. Based on the selectivity against this off-target and the analysis of the ADME-tox profile, compound 1c was selected for in vivo efficacy assessment, which demonstrated procognitive effects as shown in reversal of scopolamine induced amnesia in an elevated plus maze test in mice. Compound 3, the demethylated version of compound 1c, was profiled against a panel of 106 receptors, channels and transporters, indicating only D3 receptor as a major off-target. Compound 3 has been selected for this study over compound 1c because of the higher 5-HT6R/D2R binding ratio. These results have defined a new direction for the design of our pseudo-selective 5-HT6R antagonists.
Assuntos
Amnésia/tratamento farmacológico , Indóis/farmacologia , Piperazinas/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Sulfonas/farmacologia , Amnésia/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Modelos Moleculares , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Escopolamina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/químicaRESUMO
A stereoselective approach to the 8b-azaacenaphthylene ring system is described. This new route features a dichloroketene-enol ether [2 + 2] cycloaddition, a vinylogous Mannich reaction, and an aza-Prins cyclization as key stereoselective transformations.
Assuntos
Acenaftenos/química , Compostos Aza/química , Modelos Moleculares , Ciclização , Estrutura Molecular , EstereoisomerismoRESUMO
The isolation of a stable beta-hydrogen-containing R-PdLn-X complex (R = alkyl; X = halide) issued from a Heck reaction is reported together with some aspects of its reactivity.