RESUMEN
The amination of aryl halides has become one of the most commonly practiced C-N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C-N coupling using Et3N as a weak, soluble base, which allows a broad substrate scope that includes bromo- and chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H2O generates, after proton loss, a coordinatively unsaturated Pd-OH species that can bind amine substrate triggering intramolecular N-H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et3N. The use of a simple, commercially available ligand, PAd3, is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom cross-coupling reactions with sensitive substrates and functionality.
Asunto(s)
Aminas/química , Agua/química , Aminación , Carbono/química , Catálisis , Ligandos , Nitrógeno/química , Paladio/químicaRESUMEN
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Asunto(s)
Naftiridinas/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Administración Oral , Animales , Ingestión de Alimentos , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Farmacocinética , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Piranos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/farmacología , Unión Competitiva , Peso Corporal/efectos de los fármacos , Línea Celular , Cricetinae , Cricetulus , Cristalografía por Rayos X , Perros , Agonismo Inverso de Drogas , Ingestión de Alimentos/efectos de los fármacos , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Glucurónidos/metabolismo , Haplorrinos , Hepatocitos/metabolismo , Humanos , Ratones , Ratones Noqueados , Modelos Moleculares , Conformación Molecular , Piranos/farmacocinética , Piranos/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis, SAR and binding affinities of cannabinoid-1 receptor (CB1R) inverse agonists based on furo[2,3-b]pyridine scaffolds are described. Food intake, mechanism specific efficacy, pharmacokinetic, and metabolic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Diseño de Fármacos , Furanos/síntesis química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Benzopiranos , Perros , Furanos/química , Furanos/farmacología , Haplorrinos , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Noqueados , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/genética , Relación Estructura-ActividadRESUMEN
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Asunto(s)
Agonistas de Receptores de Cannabinoides , Obesidad/tratamiento farmacológico , Pirimidinas/química , Administración Oral , Animales , Cannabinoides/química , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Estructura Terciaria de Proteína , Ratas , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB2/agonistas , Relación Estructura-ActividadRESUMEN
Optimization of the biological activity for 5,6-diarylpyridines as CB1 receptor inverse agonists is described. Food intake and pharmacokinetic evaluation of 3f and 15c indicate that these compounds are effective orally active modulators of CB1.
Asunto(s)
Química Farmacéutica/métodos , Piridinas/química , Piridinas/síntesis química , Receptor Cannabinoide CB1/agonistas , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Conducta Alimentaria/efectos de los fármacos , Concentración 50 Inhibidora , Modelos Químicos , Conformación Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Temperatura , Tolueno/químicaRESUMEN
Synthesis, SAR, and binding affinities are described for a new class of 1,8-naphthyridinone CB1 receptor specific inverse agonists. Food intake, knockout mouse, and pharmacokinetic evaluation of 14 indicate that this compound is an effective orally active modulator of CB1.