RESUMEN
Sphingosine kinases (SphK1, SphK2) are main regulators of sphingosine-1-phosphate (S1P), which is a pleiotropic lipid mediator involved in numerous physiological and pathophysiological functions. SphKs are targets for novel anti-cancer and anti-inflammatory agents that can promote cell apoptosis and modulate autoimmune diseases. Herein, we describe the design, synthesis and evaluation of an aminothiazole class of SphK inhibitors. Potent inhibitors have been discovered through a series of modifications using the known SKI-II scaffold to define structure-activity relationships. We identified N-(4-methylthiazol-2-yl)-(2,4'-bithiazol)-2'-amine (24, ST-1803; IC50 values: 7.3 µM (SphK1), 6.5 µM (SphK2)) as a promising candidate for further in vivo investigations and structural development.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Quinasas Dependientes de Calcio-Calmodulina , Relación Dosis-Respuesta a Droga , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
Pathogens, expressing metallo-ß-lactamases (MBLs), become resistant against most ß-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of ß-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.
Asunto(s)
Descubrimiento de Drogas/métodos , Compuestos de Sulfhidrilo/aislamiento & purificación , Compuestos de Sulfhidrilo/farmacología , Inhibidores de beta-Lactamasas/aislamiento & purificación , Inhibidores de beta-Lactamasas/farmacología , Compuestos de Sulfhidrilo/síntesis química , Resistencia betalactámica/efectos de los fármacos , Inhibidores de beta-Lactamasas/síntesis químicaRESUMEN
Metabolic syndrome (MetS) is a multifactorial disease cluster that consists of dyslipidemia, cardiovascular disease, type 2 diabetes mellitus, and obesity. MetS patients are strongly exposed to polypharmacy; however, the number of pharmacological compounds required for MetS treatment can be reduced by the application of multitarget compounds. This study describes the design of dual-target ligands that target soluble epoxide hydrolase (sEH) and the peroxisome proliferator-activated receptor type γ (PPARγ). Simultaneous modulation of sEH and PPARγ can improve diabetic conditions and hypertension at once. N-Benzylbenzamide derivatives were determined to fit a merged sEH/PPARγ pharmacophore, and structure-activity relationship studies were performed on both targets, resulting in a submicromolar (sEH IC50 = 0.3 µM/PPARγ EC50 = 0.3 µM) modulator 14c. In vitro and in vivo evaluations revealed good ADME properties qualifying 14c as a pharmacological tool compound for long-term animal models of MetS.
Asunto(s)
Benzamidas/síntesis química , Benzamidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Síndrome Metabólico/tratamiento farmacológico , PPAR gamma/efectos de los fármacos , Células 3T3 , Administración Oral , Animales , Benzamidas/farmacocinética , Células COS , Chlorocebus aethiops , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/farmacocinética , Humanos , Hipertensión/tratamiento farmacológico , Técnicas In Vitro , Ratones , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Eicosanoids like leukotrienes and prostaglandins play a considerable role in inflammation. Produced within the arachidonic acid (AA) cascade, these lipid mediators are involved in the pathogenesis of pain as well as acute and chronic inflammatory diseases like rheumatoid arthritis and asthma. With regard to the lipid cross-talk within the AA pathway, a promising approach for an effective anti-inflammatory therapy is the development of inhibitors targeting more than one enzyme of this cascade. Within this study, thirty N-4-diaryl-1,3-thiazole-2-amine based compounds with different substitution patterns were synthesized and tested in various cell-based assays to investigate their activity and selectivity profile concerning five key enzymes involved in eicosanoid metabolism (5-, 12-, 15-lipoxygenase (LO), cyclooxygenase-1 and -2 (COX-1/-2)). With compound 7, 2-(4-phenyl)thiazol-2-ylamino)phenol (ST-1355), a multi-target ligand targeting all tested enzymes is presented, whereas compound 9, 2-(4-(4-chlorophenyl)thiazol-2-ylamino)phenol (ST-1705), represents a potent and selective 5-LO and COX-2 inhibitor with an IC50 value of 0.9 ± 0.2 µM (5-LO) and a residual activity of 9.1 ± 1.1% at 10 µM (COX-2 product formation). The promising characteristics and the additional non-cytotoxic profile of both compounds reveal new lead structures for the treatment of eicosanoid-mediated diseases.
Asunto(s)
Aminofenoles/farmacología , Eicosanoides/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Tiazoles/farmacología , Proteínas Activadoras de la 5-Lipooxigenasa/metabolismo , Aminofenoles/síntesis química , Aminofenoles/química , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Eicosanoides/metabolismo , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HeLa , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química , Células Tumorales Cultivadas , Células U937RESUMEN
BACKGROUND: 5-LO is an important enzyme involved in the biosynthesis of leukotrienes, which are lipid mediators of immune and inflammation responses, with important roles in respiratory disease, cardiovascular disease, immune responses and certain types of cancer. Therefore, this enzyme has been investigated as a potential target for the treatment of these pathophysiological conditions. RESULTS: 5-LO inhibitory potential was investigated in intact polymorphonuclear leukocytes, a cell-free assay, in human whole blood and rodent cells to both elucidate structure-activity relationships and in vitro pharmacological evaluation. Chemical modifications for lead optimization via straight forward synthesis was used to combine small polar groups, which led to a suitable candidate (IC50 [polymorphonuclear leukocytes] = 1.15 µM, IC50 [S100] = 0.29 µM) with desired in vitro biopharmaceutical profiles in terms of solubility (451.9 µg/ml) and intrinsic clearance without demonstrating any cytotoxicity. CONCLUSION: Compound 9l is a novel, potent and selective 5-LO inhibitor with favorable preclinical drug-like properties.
Asunto(s)
Araquidonato 5-Lipooxigenasa/química , Imidazoles/química , Inhibidores de la Lipooxigenasa/química , Piridinas/química , Animales , Araquidonato 5-Lipooxigenasa/metabolismo , Línea Celular , Análisis Mutacional de ADN , Evaluación Preclínica de Medicamentos , Humanos , Imidazoles/toxicidad , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/toxicidad , Ratones , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Piridinas/síntesis química , Piridinas/toxicidad , Salmonella/efectos de los fármacos , Salmonella/genética , Solubilidad , Relación Estructura-ActividadRESUMEN
Inspired by nature: Natural product isopropylstilbene was identified as an inhibitor of soluble epoxide hydrolase exhibiting antiproliferative properties. Following the natural product inspired design approach, a library of (E)-styryl-1H-benzo[d]imidazoles was synthesized and evaluated with recombinant enzyme and on several cancer cell lines.