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
A novel class of 1,3,5-pyrazoles has been discovered as potent human glucagon receptor antagonists. Notably, compound 26 is orally bioavailable in several preclinical species and shows selectivity towards cardiac ion channels, other family B receptors such hGIP and hGLP1, and a large panel of enzymes and additional receptors. When dosed orally, compound 26 is efficacious in suppressing glucagon induced plasma glucose excursion in rhesus monkey and transgenic murine pharmacodynamic models at 1 and 10 mpk, respectively.
Asunto(s)
Pirazoles/química , Receptores de Glucagón/antagonistas & inhibidores , Administración Oral , Animales , Glucemia/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Humanos , Macaca mulatta , Ratones , Ratones Transgénicos , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Receptores de Glucagón/metabolismo , Relación Estructura-ActividadRESUMEN
A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Asunto(s)
Fármacos Antiobesidad/uso terapéutico , Carboxiliasas/antagonistas & inhibidores , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Hipoglucemiantes/uso terapéutico , Obesidad/tratamiento farmacológico , Propanoles/uso terapéutico , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Carboxiliasas/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratones , Ratones Endogámicos C57BL , Propanoles/síntesis química , Propanoles/química , Propanoles/farmacología , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazoles/uso terapéuticoRESUMEN
Prolylcarboxypeptidase (PrCP) is a serine protease that may have a role in metabolism regulation. A class of reversible, potent, and selective PrCP inhibitors was developed starting from a mechanism based design for inhibiting this serine protease. Compound 8o inhibits human and mouse PrCP at IC(50) values of 1 and 2 nM and is not active (IC(50) > 25 µM) against a panel of closely related proteases. It has lower serum binding than its close analogues and is bioavailable in mouse. Subchronic dosing of 8o in PrCP(-/-) and WT mice at 100 mg/kg for 5 days resulted in a 5% reduction in body weight in WT mice and a 1% reduction in PrCP KO mice.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Bencimidazoles/síntesis química , Carboxipeptidasas/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Inhibidores de Serina Proteinasa/síntesis química , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Carboxipeptidasas/genética , Diseño de Fármacos , Humanos , Masculino , Ratones , Ratones Noqueados , Obesidad/tratamiento farmacológico , Obesidad/enzimología , Fenilalanina/síntesis química , Fenilalanina/farmacocinética , Fenilalanina/farmacología , Unión Proteica , Inhibidores de Serina Proteinasa/farmacocinética , Inhibidores de Serina Proteinasa/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
To discover antifungal treatments that possess the desired characteristics of broad spectrum activity, a strong safety profile, and oral bioavailability, new discovery strategies must be implemented to identify structural classes of molecules capable of combating these microorganisms. One such technique that has been implemented is the Candida albicans Fitness Test, a whole cell screening platform capable of delineating the mechanism of action of compounds that demonstrate activity against the clinically relevant pathogenic fungus, C. albicans. Screening crude natural product extracts with this technology has resulted in the identification of a novel family of antifungal natural products, named the parnafungins, which inhibit the enzyme polyadenosine polymerase (PAP), a key component of the mRNA cleavage and polyadenylation complex. Owing to the rapid interconversion of the structural and stereoisomers of the parnafungins at neutral pH, the determination of the structural isomer with the highest affinity for PAP with standard biochemical assays has not been possible. Herein, we present an application of affinity-selection/mass spectrometry (AS-MS) to determine that the "straight" parnafungin structural isomer (parnafungin A) binds preferentially to PAP compared to the "bent" structural isomer (parnafungin B).
Asunto(s)
Oxazolidinonas/química , Oxazolidinonas/metabolismo , Polinucleotido Adenililtransferasa/metabolismo , Productos Biológicos/química , Productos Biológicos/metabolismo , Cromatografía Liquida , Hongos/enzimología , Humanos , Isomerismo , Ligandos , Espectrometría de Masas , Oxazolidinonas/análisisRESUMEN
A series of HIV protease inhibitors with modifications on the P3 position have been designed and synthesized. These compounds exhibit excellent antiviral activity against both the wild type enzyme and PI-resistant clinical viral isolates. The synthesis and biological activity of the compounds are described.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Línea Celular , Farmacorresistencia Viral , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Indicadores y Reactivos , Indinavir/síntesis química , Indinavir/farmacología , Relación Estructura-ActividadRESUMEN
Affinity-based selection strategies have recently emerged as a complement to traditional high throughput screening for the rapid discovery of lead compounds for the large number of protein targets emerging from--omics technologies. Herein, we describe a method for the ranking of mixtures of ligands by affinity selection and apply it to rank order a set of inhibitors for the enzyme dipeptidyl peptidase IV.
Asunto(s)
Química Farmacéutica/métodos , Dipeptidil Peptidasa 4/química , Inhibidores Enzimáticos/síntesis química , Ligandos , Diabetes Mellitus/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Modelos QuímicosRESUMEN
A potent and selective anthrax LF inhibitor 40, (2R)-2-[(4-fluoro-3-methylphenyl)sulfonylamino]-N-hydroxy-2-(tetrahydro-2H-pyran-4-yl)acetamide, was identified through SAR study of a high throughput screen lead. It has an IC50 of 54 nM in the enzyme assay and an IC50 of 210 nM in the macrophage cytotoxicity assay. Compound 40 is also effective in vivo in several animal model studies.
Asunto(s)
Toxinas Bacterianas/antagonistas & inhibidores , Piranos/farmacología , Animales , Carbunco/tratamiento farmacológico , Carbunco/prevención & control , Antígenos Bacterianos , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos , Macaca mulatta , Metaloproteasas/antagonistas & inhibidores , Ratones , Estructura Molecular , Piranos/administración & dosificación , Piranos/síntesis química , Conejos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel class of spiro-ureas has been discovered as potent human glucagon receptor antagonists in both binding and functional assays. Preliminary studies have revealed that compound 15 is an orally active human glucagon receptor antagonist in a transgenic murine pharmacodynamic model at 10 and 30 mpk. Compound 15 is orally bioavailable in several preclinical species and shows selectivity toward cardiac ion channels and other family B receptors, such as hGIP1 and hGLP.
Asunto(s)
Receptores de Glucagón/antagonistas & inhibidores , Compuestos de Espiro/farmacología , Urea/farmacología , Administración Oral , Animales , Células CHO , Cricetinae , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Ratones Transgénicos , Modelos Moleculares , Compuestos de Espiro/química , Urea/químicaRESUMEN
Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of ezetimibe, we have developed a binding assay and shown that labeled ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.
Asunto(s)
Azetidinas/farmacología , Proteínas de la Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas/metabolismo , Animales , Azetidinas/química , Sitios de Unión , Línea Celular , Membrana Celular/metabolismo , Enterocitos/citología , Enterocitos/metabolismo , Ezetimiba , Humanos , Mucosa Intestinal/metabolismo , Intestinos/citología , Macaca mulatta , Proteínas de la Membrana/genética , Proteínas de Transporte de Membrana/deficiencia , Proteínas de Transporte de Membrana/genética , Ratones , Ratones Endogámicos C57BL , Microvellosidades/metabolismo , Enfermedades de Niemann-Pick , Unión Proteica , Proteínas/genética , Ratas , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
A novel class of antagonists of the human glucagon receptor (hGCGR) has been discovered. Systematic modification of the lead compound identified substituents that were essential for activity and those that were amenable to further optimization. This SAR exploration resulted in the synthesis of 13, which exhibited good potency as an hGCGR functional antagonist (IC50 = 34 nM) and moderate bioavailability (36% in mice).
Asunto(s)
Receptores de Glucagón/antagonistas & inhibidores , Tiofenos/síntesis química , Tiofenos/farmacología , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiofenos/clasificaciónRESUMEN
Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. Hyperglucagonemia and/or an elevated glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the glucagon receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125I-labeled glucagon to the human glucagon receptor with a half-maximal inhibitory concentration value of 181 +/- 10 nmol/l. In CHO cells overexpressing the human glucagon receptor, Cpd 1 increased the half-maximal effect for glucagon stimulation of adenylyl cyclase with a KDB of 81 +/- 11 nmol/l. In addition, Cpd 1 blocked glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking glucagon-induced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous glucagon. Taken together, these data suggest that Cpd 1 is a potent glucagon receptor antagonist that has the capability to block the effects of glucagon in vivo.
Asunto(s)
Glucagón/antagonistas & inhibidores , Receptores de Glucagón/antagonistas & inhibidores , Adenilil Ciclasas/metabolismo , Animales , Células CHO , Cricetinae , Glucagón/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Cinética , Glucógeno Hepático/metabolismo , Masculino , Ratones , Ratones TransgénicosRESUMEN
HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , VIH-1/efectos de los fármacos , Oxadiazoles/química , Línea Celular Tumoral , Farmacorresistencia Viral Múltiple , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/enzimología , VIH-1/aislamiento & purificación , Humanos , Indinavir/análogos & derivados , Indinavir/síntesis química , Indinavir/química , Indinavir/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Piridinas/química , EstereoisomerismoRESUMEN
Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacocinética , Animales , Fármacos Anti-VIH/química , División Celular/efectos de los fármacos , Células HeLa , Humanos , Estructura Molecular , Piperidinas/química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/síntesis química , Piperidinas/farmacocinética , Acetatos/química , Acetatos/farmacocinética , Administración Oral , Animales , Fármacos Anti-VIH/química , Disponibilidad Biológica , Perros , Células HeLa , Humanos , Macaca mulatta , Estructura Molecular , Monocitos/efectos de los fármacos , Piperidinas/química , Pirazoles/química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Extensive SAR studies in our benzylpyrazole series of CCR5 antagonists have shown that both lipophilic and hydrophilic substituents on the phenyl of the benzyl group increase antiviral potency. However, improvements in pharmacokinetic profiles were generally only observed with more lipophilic substitutions. 4-Biphenyl (51) performed the best in this regard. Highly lipophilic substituents impart undesirable ion channel activity to these CCR5 antagonists. Alkoxy substituents provide a good balance of antiviral activity, pharmacokinetic parameters, and selectivity. Compounds 42b and 42d, containing a 3,4-dimethoxy substituent, are considered the most promising improvements over parent compounds 9. They demonstrate improved antiviral activity while retaining good pharmacokinetic profile and selectivity.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Antagonistas de los Receptores CCR5 , Piperidinas/química , Piperidinas/farmacocinética , Pirazoles/química , Animales , Fármacos Anti-VIH/síntesis química , Disponibilidad Biológica , Perros , Células HeLa , Humanos , Estructura Molecular , Monocitos/efectos de los fármacos , Piperidinas/síntesis química , Pirazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Quinolinas/síntesis química , Quinolinas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Cinética , Modelos Moleculares , Conformación Molecular , Quinolinas/química , Relación Estructura-ActividadRESUMEN
HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , Indinavir/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Administración Oral , Biotransformación , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/metabolismo , Diseño de Fármacos , Farmacorresistencia Viral , Quimioterapia Combinada , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Indinavir/farmacología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Pirroles/síntesis química , Pirroles/farmacología , Relación Estructura-ActividadRESUMEN
Transposition of the pyridyl nitrogen from the P(3) substituent to the P(1)' substituent in HIV-1 protease inhibitors (PI) affords compounds such as 3 with an improved inhibitory profile against multiple P450 isoforms. These compounds also displayed increased potency, with 3 inhibiting viral spread (CIC(95)) at <8 nM for every strain of PI-resistant HIV-1 tested. The poor to modest bioavailability of these compounds may correlate in part to their aqueous solubility.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Animales , Perros , Farmacorresistencia Viral/efectos de los fármacos , Farmacorresistencia Viral/fisiología , Inhibidores de la Proteasa del VIH/administración & dosificación , HumanosRESUMEN
The synthesis of a series of novel dihdyropyridine diacid glycogen phosphorylase inhibitors is presented. SAR and functional assay data are discussed, along with the effect of a single inhibitor on blood glucose in a diabetic animal model.