RESUMEN
A series of GPR119 agonists based on a 2,6-diazatricyclo[3.3.1.1â¼3,7â¼]decane ring system is described. Also provided is a detailed account of the development of a multigram scale synthesis of the diazatricyclic ring system, which was achieved using a Hofmann-Löffler-Freytag reaction as the key step. The basis for the use of this complex framework lies in an attempt to constrain one end of the molecule in the "agonist conformation" as was previously described for 3-oxa-7-aza-bicyclo[3.3.1]nonanes. Optimization of carbamate analogues of the diazatricylic compounds led to the identification of 32i as a potent agonist of the GPR119 receptor with low unbound human liver microsomal clearance. The use of an agonist response weighted ligand lipophilic efficiency (LLE) termed AgLLE is discussed along with the issues of applying efficiency measures to agonist programs. Ultimately, solubility limited absorption and poor exposure reduced further interest in these molecules.
Asunto(s)
Compuestos Aza/síntesis química , Hidrocarburos Aromáticos con Puentes/síntesis química , Ciclodecanos/síntesis química , Receptores Acoplados a Proteínas G/agonistas , Animales , Compuestos Aza/química , Compuestos Aza/farmacología , Disponibilidad Biológica , Hidrocarburos Aromáticos con Puentes/química , Hidrocarburos Aromáticos con Puentes/farmacología , Cristalografía por Rayos X , Ciclodecanos/química , Ciclodecanos/farmacología , Perros , Diseño de Fármacos , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/química , Solubilidad , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Glucokinase is a key regulator of glucose homeostasis, and small molecule allosteric activators of this enzyme represent a promising opportunity for the treatment of type 2 diabetes. Systemically acting glucokinase activators (liver and pancreas) have been reported to be efficacious but in many cases present hypoglycaemia risk due to activation of the enzyme at low glucose levels in the pancreas, leading to inappropriately excessive insulin secretion. It was therefore postulated that a liver selective activator may offer effective glycemic control with reduced hypoglycemia risk. Herein, we report structure-activity studies on a carboxylic acid containing series of glucokinase activators with preferential activity in hepatocytes versus pancreatic ß-cells. These activators were designed to have low passive permeability thereby minimizing distribution into extrahepatic tissues; concurrently, they were also optimized as substrates for active liver uptake via members of the organic anion transporting polypeptide (OATP) family. These studies lead to the identification of 19 as a potent glucokinase activator with a greater than 50-fold liver-to-pancreas ratio of tissue distribution in rodent and non-rodent species. In preclinical diabetic animals, 19 was found to robustly lower fasting and postprandial glucose with no hypoglycemia, leading to its selection as a clinical development candidate for treating type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/síntesis química , Glucoquinasa/metabolismo , Hepatocitos/metabolismo , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Ácidos Nicotínicos/síntesis química , Sitio Alostérico , Animales , Glucemia/metabolismo , Perros , Activadores de Enzimas/farmacocinética , Activadores de Enzimas/farmacología , Haplorrinos , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Imidazoles/farmacocinética , Imidazoles/farmacología , Técnicas In Vitro , Células Secretoras de Insulina/metabolismo , Masculino , Modelos Moleculares , Ácidos Nicotínicos/farmacocinética , Ácidos Nicotínicos/farmacología , Transportadores de Anión Orgánico/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
Analogues related to dirlotapide (1), a gut-selective inhibitor of microsomal triglyceride transfer protein (MTP) were prepared with the goal of further reducing the potential for unwanted liver MTP inhibition and associated side-effects. Compounds were designed to decrease active metabolite load: reducing MTP activity of likely human metabolites and increasing metabolite clearance to reduce exposure. Introduction of 4'-alkyl and 4'-alkoxy substituents afforded compounds exhibiting improved therapeutic index in rats with respect to liver triglyceride accumulation and enzyme elevation. Likely human metabolites of select compounds were prepared and characterized for their potential to inhibit MTP in vivo. Based on preclinical efficacy and safety data and its potential for producing short-lived, weakly active metabolites, compound 13 (PF-02575799) advanced into phase 1 clinical studies.
Asunto(s)
Aminoquinolinas/química , Benzamidas/química , Carbamatos/metabolismo , Proteínas Portadoras/antagonistas & inhibidores , Indoles/metabolismo , Aminoquinolinas/síntesis química , Aminoquinolinas/farmacocinética , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Carbamatos/síntesis química , Carbamatos/farmacocinética , Proteínas Portadoras/metabolismo , Perros , Evaluación Preclínica de Medicamentos , Humanos , Indoles/síntesis química , Indoles/farmacocinética , Microsomas Hepáticos/metabolismo , Ratas , Triglicéridos/metabolismoRESUMEN
Screening Pfizer's compound library resulted in the identification of weak acetyl-CoA carboxylase inhibitors, from which were obtained rACC1 CT-domain co-crystal structures. Utilizing HTS hits and structure-based drug discovery, a more rigid inhibitor was designed and led to the discovery of sub-micromolar, spirochromanone non-specific ACC inhibitors. Low nanomolar, non-specific ACC-isozyme inhibitors that exhibited good rat pharmacokinetics were obtained from this chemotype.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Modelos Moleculares , Ratas , Bibliotecas de Moléculas Pequeñas/farmacocinética , Relación Estructura-ActividadRESUMEN
A promising area of novel anti-diabetic therapy involves identification of small molecule activators of the glucokinase enzyme to reduce blood glucose and normalize glucose stimulated insulin secretion. Herein, we report the identification and optimization of a series of 4-sulfonyl-2-pyridone activators. The activators were evaluated for in vitro biochemical activation and pharmacokinetic properties. As part of these efforts, a unique metabolic liability of the 4-sulfonyl-2-pyridone ring system was identified wherein this heterocycle readily undergoes conjugation with glutathione under non-enzymatic conditions.
Asunto(s)
Glucoquinasa/efectos de los fármacos , Hipoglucemiantes/farmacocinética , Piridonas/farmacocinética , Animales , Glucemia , Activación Enzimática/efectos de los fármacos , Glutatión/química , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/metabolismo , Microsomas Hepáticos/metabolismo , Piridonas/química , Piridonas/metabolismo , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The structure-activity relationship toward canine COX-1 and COX-2 in vitro whole blood activity of 4-hydrogen versus 4-cyano substituted 5-aryl or 5-heteroatom substituted N-phenyl versus N-2-pyridyl sulfone pyrazoles is discussed. The differences between the pairs of compounds with the 4-nitrile pyrazole derivatives having substantially improved in vitro activity are highlighted for both COX-2 and COX-1. This difference in activity may be due to the contribution of the hydrogen bond of the 4-cyano group with Ser 530 as shown by our molecular modeling studies. In addition, our model suggests a potential contribution from hydrogen bonding of the pyridyl nitrogen to Tyr 355 for the increased activity over the phenyl sulfone analogs.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Nitrilos/química , Nitrilos/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/química , Piridinas/farmacología , Sulfonas/química , Sulfonas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Celecoxib , Ciclooxigenasa 1/metabolismo , Perros , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Indicadores y Reactivos , Cinética , Modelos Moleculares , Relación Estructura-Actividad , Sulfonamidas/farmacologíaRESUMEN
The discovery of heteroaryl-phenyl-substituted pyrazole derivatives as canine selective COX-2 inhibitors is described. Structure-activity relationship (SAR) studies of this class of compounds led to the identification of compound 1 which demonstrated a canine whole blood COX-2 inhibitory IC50 of 12 nM and selectivity ratio of COX-1/COX-2 greater than 4000-fold.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Pirazoles/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/farmacología , Perros , Concentración 50 Inhibidora , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies of novel 2-[3-trifluoromethyl-5-alkyl(thio)ether pyrazo-1-yl]-5-methanesulfonyl pyridine derivatives for canine COX enzymes are described. The 4-cyano-5-alkyl ethers were found to have excellent potency and selectivity, whereas the 5-thioethers were potent but less selective than the ether analogs in a canine whole blood (CWB) COX-2 assay.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Éteres/química , Pirazoles/química , Compuestos de Sulfhidrilo/química , Alquilación , Animales , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Perros , Concentración 50 Inhibidora , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies of the novel 2-[3-di and trifluoromethyl-5-alkylamino pyrazo-1-yl]-5-methanesulfonyl (SO(2)Me)/sulfamoyl (SO(2)NH(2))-pyridine derivatives for canine COX enzymes are described. The studies led to the identification of 2e as lead with potent in vitro activity, selectivity, and in vivo activity in dogs and cats.
Asunto(s)
Inhibidores de la Ciclooxigenasa 2 , Ciclooxigenasa 2/efectos de los fármacos , Pirazoles , Administración Oral , Animales , Gatos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacocinética , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirazoles/farmacocinética , Relación Estructura-ActividadRESUMEN
Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.
Asunto(s)
Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/química , Isoenzimas/antagonistas & inhibidores , Piridinas/administración & dosificación , Piridinas/química , Administración Oral , Animales , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Perros , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintasas/metabolismo , Relación Estructura-ActividadRESUMEN
Aryl and hetero aryl substituted 3,6-ketals of 15-membered azalide analogues were synthesized and were found to have potent in vitro antibacterial activity against veterinary pathogens, including Staphylococcus aureus and Pasteurella multocida.