RESUMEN
A depressed autophagy has previously been reported in cystic fibrosis patients with the common F508del-CFTR mutation. This report describes the synthesis and preliminary biological characterization of a novel series of autophagy activators involving fatty acid cysteamine conjugates. These molecular entities were synthesized by first covalently linking cysteamine to docosahexaenoic acid. The resulting conjugate 1 synergistically activated autophagy in primary homozygous F508del-CFTR human bronchial epithelial (hBE) cells at submicromolar concentrations. When conjugate 1 was used in combination with the corrector lumacaftor and the potentiator ivacaftor, it showed an additive effect, as measured by the increase in the chloride current in a functional assay. In order to obtain a more stable form for oral dosing, the sulfhydryl group in conjugate 1 was converted into a functionalized disulfide moiety. The resulting conjugate 5 is orally bioavailable in the mouse, rat, and dog and allows a sustained delivery of the biologically active conjugate 1.
Asunto(s)
Autofagia/efectos de los fármacos , Cisteamina/farmacología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Ácidos Grasos/química , Cisteamina/química , Pliegue de ProteínaRESUMEN
CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9. Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased. In apolipoprotein E*3-Leiden mice fed a cholesterol-containing western diet, CAT-2003 decreased hepatic inflammation and steatosis as evidenced by fewer inflammatory cell aggregates in histopathologic sections, decreased nuclear factor kappa B activity in liver lysates, reduced inflammatory gene expression, reduced intrahepatic cholesteryl ester and triglyceride levels, and decreased liver mass. Plasma PCSK9 was reduced and hepatic low-density lipoprotein receptor protein expression was increased; plasma cholesterol and triglyceride levels were lowered. Aortic root segments showed reduction of several atherosclerotic markers, including lesion size, number, and severity. CAT-2003, when dosed in combination with atorvastatin, further lowered plasma cholesterol levels and decreased hepatic expression of SREBP target genes. Conclusion: SREBP inhibition is a promising new strategy for the prevention and treatment of diseases associated with abnormal lipid metabolism, such as atherosclerosis and nonalcoholic steatohepatitis. (Hepatology Communications 2017;1:311-325).
RESUMEN
This report describes the synthesis and preliminary biological characterization of novel fatty acid niacin conjugates and fatty acid salicylate conjugates. These molecular entities were created by covalently linking two bioactive molecules, either niacin or salicylic acid, to an omega-3 fatty acid. This methodology allows the simultaneous intracellular delivery of two bioactives in order to elicit a pharmacological response that could not be replicated by administering the bioactives individually or in combination. The fatty acid niacin conjugate 5 has been shown to be an inhibitor of the sterol regulatory element binding protein (SREBP), a key regulator of cholesterol metabolism proteins such as PCSK9, HMG-CoA reductase, ATP citrate lyase, and NPC1L1. On the other hand, the fatty acid salicylate conjugate 11 has been shown to have a unique anti-inflammatory profile based on its ability to modulate the NF-κB pathway through the intracellular release of the two bioactives.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Ácidos Grasos/química , Niacina/química , Niacina/farmacología , Ácido Salicílico/química , Ácido Salicílico/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Línea Celular , Perros , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Hidrólisis , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Estructura Molecular , FN-kappa B/antagonistas & inhibidores , FN-kappa B/metabolismo , Niacina/administración & dosificación , Ratas , Ratas Sprague-Dawley , Ácido Salicílico/administración & dosificación , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/antagonistas & inhibidores , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
SIRT1 is an NAD(+)-dependent protein deacetylase that appears to produce beneficial effects on metabolic parameters such as glucose and insulin homeostasis. Activation of SIRT1 by resveratrol (1) has been shown to modulate insulin resistance, increase mitochondrial content and prolong survival in lower organisms and in mice on a high fat diet. Herein, we describe the identification and SAR of a series of oxazolo[4,5-b]pyridines as novel small molecule activators of SIRT1 which are structurally unrelated to and more potent than resveratrol.
Asunto(s)
Oxazoles/síntesis química , Oxazoles/metabolismo , Piridinas/síntesis química , Piridinas/metabolismo , Sirtuinas/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Humanos , Ratones , Ratones Transgénicos , Oxazoles/farmacología , Piridinas/farmacología , Ratas , Ratas Zucker , Sirtuina 1 , Sirtuinas/agonistas , Relación Estructura-ActividadRESUMEN
A series of triamide derivatives bearing a benzothiazole core is shown to be potent microsomal triglyceride transfer protein (MTP) inhibitors. In order to minimize liver toxicity, these compounds have been optimized to have activity only in the enterocytes and have limited systemic bioavailability. Upon oral administration, selected analogs within this series have been further demonstrated to reduce food intake along with body weight and thereby improve glucose homeostasis and insulin sensitivity in a 28-day mice diet-induced obesity (DIO) model.
Asunto(s)
Benzotiazoles/química , Proteínas Portadoras/antagonistas & inhibidores , Descubrimiento de Drogas , Enterocitos/metabolismo , Animales , Benzotiazoles/farmacología , Benzotiazoles/uso terapéutico , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Enterocitos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.
Asunto(s)
Activadores de Enzimas/síntesis química , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Quinoxalinas/síntesis química , Sirtuina 1/metabolismo , Tiazoles/síntesis química , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Imidazoles/química , Imidazoles/farmacología , Ratones , Quinoxalinas/química , Quinoxalinas/farmacología , Ratas , Ratas Zucker , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
Asunto(s)
Restricción Calórica , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Sirtuinas/agonistas , Acetilación , Sitio Alostérico , Animales , Glucemia/metabolismo , Dominio Catalítico , Línea Celular , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Modelos Animales de Enfermedad , Drosophila melanogaster , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Insulina/metabolismo , Insulina/farmacología , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Resveratrol , Sirtuina 1 , Sirtuinas/metabolismo , Estilbenos/química , Estilbenos/farmacologíaRESUMEN
Novel tricyclic imidazoline antagonists of the adenosine A1 receptor are described. For key compounds, the selectivity level over other adenosine receptor subtypes is examined along with their in vivo effects in a rat diuresis model. Compound 14, the (R)-isomer of 7,8-dihydro-8-ethyl-2-(4-bicyclo[2.2.2]octan-1-ol)-4-propyl-1H-imidazo[2,1-i]purin-5(4H)-one, is a particularly potent adenosine A1 receptor antagonist with good selectivity over the other three adenosine receptor subtypes: A1 (human) Ki=22 nM; A2A (human) Ki=4400 nM; A2B (human) Ki=580 nM; A3 (human) Ki>or=10,000 nM. Imidazoline 14 is a competitive adenosine A1 receptor antagonist with a pA2 value of 8.88 and is highly soluble in water (>100 mg/mL). In addition, it has an oral bioavailability of 84% and an oral half-life of 3.8 h in rats. When orally administered in a rat diuresis model, compound 14 promoted sodium excretion (ED50=0.01 mg/kg). This level of efficacy is comparable to that of BG9928, a selective adenosine A1 receptor antagonist that is currently in clinical trials as a treatment for congestive heart failure. Additional modifications to 14 also showed that the bridgehead hydroxyl group could be replaced with a propionic acid (compound 36) without a significant loss in binding affinity or in vivo activity.
Asunto(s)
Antagonistas del Receptor de Adenosina A1 , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Imidazolinas/síntesis química , Purinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Corteza Cerebral/metabolismo , Cuerpo Estriado/metabolismo , Semivida , Atrios Cardíacos/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Imidazolinas/farmacocinética , Imidazolinas/farmacología , Técnicas In Vitro , Natriuresis/efectos de los fármacos , Purinas/farmacocinética , Purinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores de Adenosina A2/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In recent years, the adenosine A2A receptor has gained interest as a potential therapeutic target for alleviating the symptoms of Parkinson's disease. Adenosine A2A receptor antagonists are orally effective in a variety of rodent models of Parkinson's disease. Traditionally, adenosine A2A, receptor antagonists are divided into two general classes, xanthine or non-xanthine derivatives. Extensive optimization among the xanthine derivatives has already led to the clinical candidate KW-6002 (Kyowa Hakko Kogyo Co Ltd). However, there is increasing interest among researchers in this field to explore other classes of compounds as potential antagonists for this particular receptor. This review highlights the more recent developments in the design and optimization of non-xanthine derivatives as adenosine A2A receptor antagonists.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Animales , Diseño de Fármacos , Humanos , Triazinas/química , Triazinas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been demonstrated to be potent and selective adenosine A(2a) receptor antagonists with oral activity in rodent models of Parkinson's disease. We have replaced the piperazinyl group with a variety of linear, monocyclic, and bicyclic diamines. Of these diamines, (R)-2-(aminomethyl)pyrrolidine is a particularly potent and selective replacement for the piperazinyl group. With this diamine component, we have been able to prepare numerous analogues with low nanomolar affinity toward the A(2a) receptor and good selectivity with respect to the A(1) receptor (>200-fold in some cases). Selected analogues from this series of [1,2,4]triazolo[1,5-a][1,3,5]triazine have now been shown to be orally active in the mouse catalepsy model.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Diaminas/síntesis química , Pirrolidinas/síntesis química , Triazinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Antiparkinsonianos/química , Antiparkinsonianos/farmacología , Unión Competitiva , Disponibilidad Biológica , Catalepsia/tratamiento farmacológico , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Técnicas Químicas Combinatorias , Diaminas/química , Diaminas/farmacología , Técnicas In Vitro , Masculino , Ratones , Pirrolidinas/química , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Triazinas/química , Triazinas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
A series of bicyclic piperazine derivatives of triazolotriazine and triazolopyrimidines was synthesized. Some of these analogues show high affinity and excellent selectivity for adenosine A(2a) receptor versus the adenosine A(1) receptor. Structure-activity-relationship (SAR) studies based on octahydropyrrolo[1,2-a]pyrazine and octahydropyrido[1,2-a]pyrazine with various capping groups are reported. Among these analogues, the most potent and selective A(2a) antagonist 26 h has a K(i) value of 0.2 nM and is 16 500-fold selective with respect to the A(1) receptor. Among a number of compounds tested, compounds 21a and 21c exhibited significantly improved metabolic stability. Compounds 21a, 21c, and 18a showed good oral efficacy in rodent catalepsy models of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Piperazinas/síntesis química , Pirimidinas/síntesis química , Triazinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Estabilidad de Medicamentos , Técnicas In Vitro , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Estructura Molecular , Enfermedad de Parkinson/tratamiento farmacológico , Piperazinas/química , Piperazinas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
Piperazine derivatives of 2-furanyl[1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We now demonstrate that potent and selective A(2a) receptor antagonists could still be obtained when the arylpiperazines are separated from the triazolotriazine core structure by an ethylenediamine spacer. Selected analogs bearing this triazolotriazine or the related triazolopyrimidine core structure have been found to be orally active in a mouse catalepsy model of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Animales , Antiparkinsonianos/farmacología , Ratones , Pirimidinas/síntesis química , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/farmacología , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
Piperazine and (R)-2-(aminomethyl)pyrrolidine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine have recently been shown to be potent and selective adenosine A(2a) receptor antagonists. We have replaced the triazolotriazine core structure with two different heterocyclic cores. One of these, the one deriving from [1,2,4]triazolo[1,5-c]pyrimidine, appears to be particularly effective and selected analogs from this series have been shown to be orally active in a mouse catalepsy model of Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/farmacología , Animales , Catalepsia/tratamiento farmacológico , Ratones , Pirimidinas/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Triazinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Antiparkinsonianos/química , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Encéfalo/metabolismo , Catalepsia/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Técnicas In Vitro , Masculino , Ratones , Trastornos Parkinsonianos/tratamiento farmacológico , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Adenosina A2A/metabolismo , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.