RESUMEN
Metabolic dysregulation and mitochondrial dysfunction are important features of acute and chronic tissue injury across species, and human genetics and preclinical data suggest that the master metabolic regulator 5'-adenosine monophosphate-activated protein kinase (AMPK) may be an effective therapeutic target for chronic kidney disease (CKD). We have recently disclosed a pan-AMPK activator, MK-8722, that was shown to have beneficial effects in preclinical models. In this study we investigated the effects of MK-8722 in a progressive rat model of diabetic nephropathy to determine whether activation of AMPK would be of therapeutic benefit. We found that MK-8722 administration in a therapeutic paradigm is profoundly renoprotective, as demonstrated by a reduction in proteinuria (63% decrease in MK-8722 10 mg/kg per day compared with vehicle group) and a significant improvement in glomerular filtration rate (779 and 430 µl/min per gram kidney weight in MK-8722 10 mg/kg per day and vehicle group, respectively), as well as improvements in kidney fibrosis. We provide evidence that the therapeutic effects of MK-8722 may be mediated by modulation of renal mitochondrial quality control as well by attenuating fibrotic and lipotoxic mechanisms in kidney cells. MK-8722 (10 mg/kg per day compared with vehicle group) achieved modest blood pressure reduction (10 mmHg lower for mean blood pressure) and significant metabolic improvements (decreased plasma glucose, triglyceride, and body weight) that could contribute to renoprotection. These data further validate the concept that targeting metabolic dysregulation in CKD could be a potential therapeutic approach. SIGNIFICANCE STATEMENT: We demonstrate in the present study that the pharmacological activation of AMPK using a small-molecule agent provided renoprotection and improved systemic and cellular metabolism. We further indicate that modulation of renal mitochondrial quality control probably contributed to renoprotection and was distinct from the effects of enalapril. Our findings suggest that improving renal mitochondrial biogenesis and function and attenuating fibrosis and lipotoxicity by targeting key metabolic nodes could be a potential therapeutic approach in management of CKD that could complement the current standard of care.
Asunto(s)
Nefropatías Diabéticas/metabolismo , Hipoglucemiantes/uso terapéutico , Imidazoles/uso terapéutico , Proteínas Quinasas/metabolismo , Piridinas/uso terapéutico , Quinasas de la Proteína-Quinasa Activada por el AMP , Anciano , Animales , Bencimidazoles , Glucemia/metabolismo , Presión Sanguínea , Células Cultivadas , Nefropatías Diabéticas/tratamiento farmacológico , Femenino , Tasa de Filtración Glomerular , Humanos , Hipoglucemiantes/farmacología , Imidazoles/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Masculino , Persona de Mediana Edad , Mitocondrias/efectos de los fármacos , Piridinas/farmacología , Ratas , Ratas Zucker , Triglicéridos/sangreRESUMEN
A new structural class of potent prolylcarboxypeptidase (PrCP) inhibitors was discovered by high-throughput screening. The series possesses a tractable SAR profile with sub-nanomolar in vitro IC(50) values. Compared to prior inhibitors, the new series demonstrated minimal activity shifts in pure plasma and complete ex vivo plasma target engagement in mouse plasma at the 20 h post-dose time point (po). In addition, the in vivo level of CNS and non-CNS drug exposure was measured.
Asunto(s)
Carboxipeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos , Animales , Butanoles/síntesis química , Butanoles/química , Butanoles/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Obesidad/tratamiento farmacológico , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacologíaRESUMEN
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Asunto(s)
Piperazinas/química , Receptor de Melanocortina Tipo 4/agonistas , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Haplorrinos , Ratones , Obesidad/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
SAR around non-peptidic potent bombesin receptor subtype-3 (BRS-3) agonist lead 2 is presented. Attempts to replace the carboxylic acid with heterocyclic isosteres to improve oral bioavailability and brain penetration are described.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Imidazoles/química , Receptores de Bombesina/agonistas , Administración Oral , Animales , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Encéfalo/metabolismo , Humanos , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Ratones , Obesidad/tratamiento farmacológico , Ratas , Receptores de Bombesina/metabolismo , Relación Estructura-ActividadRESUMEN
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Asunto(s)
Ligandos , Receptor de Melanocortina Tipo 4/agonistas , Animales , Humanos , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Asunto(s)
Piperidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Encéfalo/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Asunto(s)
Obesidad/tratamiento farmacológico , Receptor de Melanocortina Tipo 4/agonistas , Triazoles/farmacología , Animales , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptor de Melanocortina Tipo 4/genética , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Receptores de Bombesina/agonistas , Animales , Disponibilidad Biológica , Humanos , Imidazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Indanos/química , Indanos/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacología , Masculino , Ratones , Estructura Molecular , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Asunto(s)
Imidazoles/química , Imidazoles/uso terapéutico , Obesidad/tratamiento farmacológico , Receptores de Bombesina/agonistas , Receptores de Bombesina/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Asunto(s)
Amidas/química , Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Pirrolidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Compuestos de Espiro/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Humanos , Ratones , Ratones Noqueados , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
Fibrosis, or the accumulation of extracellular matrix, is a common feature of many chronic diseases. To interrogate core molecular pathways underlying fibrosis, we cross-examine human primary cells from various tissues treated with TGF-ß, as well as kidney and liver fibrosis models. Transcriptome analyses reveal that genes involved in fatty acid oxidation are significantly perturbed. Furthermore, mitochondrial dysfunction and acylcarnitine accumulation are found in fibrotic tissues. Substantial downregulation of the PGC1α gene is evident in both in vitro and in vivo fibrosis models, suggesting a common node of metabolic signature for tissue fibrosis. In order to identify suppressors of fibrosis, we carry out a compound library phenotypic screen and identify AMPK and PPAR as highly enriched targets. We further show that pharmacological treatment of MK-8722 (AMPK activator) and MK-4074 (ACC inhibitor) reduce fibrosis in vivo. Altogether, our work demonstrate that metabolic defect is integral to TGF-ß signaling and fibrosis.
Asunto(s)
Fibrosis/genética , Fibrosis/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Adenilato Quinasa/metabolismo , Animales , Bencimidazoles/farmacología , Células Cultivadas , Matriz Extracelular/metabolismo , Matriz Extracelular/patología , Expresión Génica/genética , Perfilación de la Expresión Génica/métodos , Humanos , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Especificidad de Órganos/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Transcriptoma/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/metabolismo , Hígado/metabolismo , Músculo Esquelético/metabolismo , Miocardio/metabolismo , Animales , Metabolismo Energético , Activación Enzimática/efectos de los fármacos , Ácidos Grasos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Homeostasis , Ratones Endogámicos C57BL , Oxidación-Reducción , Condicionamiento Físico AnimalRESUMEN
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , TelomerasaRESUMEN
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a key regulator of mammalian energy homeostasis and has been implicated in mediating many of the beneficial effects of exercise and weight loss including lipid and glucose trafficking. As such, the enzyme has long been of interest as a target for the treatment of Type 2 Diabetes Mellitus. We describe the optimization of ß1-selective, liver-targeted AMPK activators and their evolution into systemic pan-activators capable of acutely lowering glucose in mouse models. Identifying surrogates for the key acid moiety in early generation compounds proved essential in improving ß2-activation and in balancing improvements in plasma unbound fraction while avoiding liver sequestration.
RESUMEN
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Bencimidazoles/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Administración Oral , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , RatonesRESUMEN
5'-Adenosine monophosphate-activated protein kinase (AMPK) is a master regulator of energy homeostasis in eukaryotes. Despite three decades of investigation, the biological roles of AMPK and its potential as a drug target remain incompletely understood, largely because of a lack of optimized pharmacological tools. We developed MK-8722, a potent, direct, allosteric activator of all 12 mammalian AMPK complexes. In rodents and rhesus monkeys, MK-8722-mediated AMPK activation in skeletal muscle induced robust, durable, insulin-independent glucose uptake and glycogen synthesis, with resultant improvements in glycemia and no evidence of hypoglycemia. These effects translated across species, including diabetic rhesus monkeys, but manifested with concomitant cardiac hypertrophy and increased cardiac glycogen without apparent functional sequelae.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Cardiomegalia/inducido químicamente , Glucosa/metabolismo , Homeostasis/efectos de los fármacos , Imidazoles/farmacología , Piridinas/farmacología , Animales , Bencimidazoles , Glucemia/efectos de los fármacos , Ayuno , Glucógeno/metabolismo , Hipoglucemia/inducido químicamente , Imidazoles/efectos adversos , Imidazoles/química , Insulina/farmacología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Piridinas/efectos adversos , Piridinas/químicaRESUMEN
Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.
Asunto(s)
Isoquinolinas/síntesis química , Receptores de Corticotropina/agonistas , Tetrahidroisoquinolinas , Triazoles/síntesis química , Animales , Unión Competitiva , Disponibilidad Biológica , Células CHO , Cricetinae , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Isoquinolinas/química , Isoquinolinas/farmacología , Conformación Molecular , Erección Peniana/efectos de los fármacos , Ratas , Receptor de Melanocortina Tipo 3 , Receptor de Melanocortina Tipo 4 , Receptores de Melanocortina , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
RESUMEN
Genetic and pharmacological studies, involving both animals and humans, suggest that the central MC4 receptor plays a key role in homeostatic control, most probably via regulation of appetite and energy expenditure. This has stimulated intense research efforts in the field of drug discovery to identify MC4 receptor agonists and antagonists for the therapeutic treatment of obesity and diseases associated with loss of body weight. This article constitutes a near comprehensive review of the published scientific literature on small molecule ligands of the hMC4 receptor since 2002.