RESUMEN
A novel series of benzenesulfonanilide derivatives of 11ß-HSD1 inhibitors were identified via modification of the sulfonamide core of the arylsulfonylpiperazine lead structures. The synthesis, in vitro biological evaluation, and structure-activity relationship of these compounds are presented. Optimization of this series rapidly resulted in the discovery of compounds (S)-10 and (S)-23 (11ß-HSD1 SPA IC(50)=1.8 and 1.4 nM, respectively).
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Anilidas/química , Compuestos de Anilina/química , Inhibidores Enzimáticos/química , Piperazinas/química , Sulfonamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/farmacología , Anilidas/síntesis química , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Células HEK293 , Humanos , Conformación Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , TransfecciónRESUMEN
The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11ß-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/química , Inhibidores Enzimáticos/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Benzamidas/síntesis química , Benzamidas/farmacocinética , Sitios de Unión , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
In this communication, human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibitory activities of a novel series of diarylsulfones are described. Optimization of this series resulted in several highly potent 11ß-HSD1 inhibitors with excellent pharmacokinetic (PK) properties. Compound (S)-25 showed excellent efficacy in a non-human primate ex vivo pharmacodynamic model.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Sulfonas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Farmacocinética , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacocinéticaRESUMEN
The synthesis and SAR of a series of arylsulfonylpiperazine inhibitors of 11beta-HSD1 are described. Optimization rapidly led to potent, selective, and orally bioavailable inhibitors demonstrating efficacy in a cynomolgus monkey ex vivo enzyme inhibition model.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Ácidos Arilsulfónicos/síntesis química , Piperazinas/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Ácidos Arilsulfónicos/clasificación , Ácidos Arilsulfónicos/farmacología , Disponibilidad Biológica , Línea Celular , Cristalografía por Rayos X , Estabilidad de Enzimas/efectos de los fármacos , Estabilidad de Enzimas/fisiología , Humanos , Macaca fascicularis , Ratones , Piperazinas/clasificación , Piperazinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
Novel 4,4-disubstituted cyclohexylbenzamide inhibitors of 11beta-HSD1 were optimized to account for liabilities relating to in vitro pharmacokinetics, cytotoxicity and protein-related shifts in potency. A representative compound showing favorable in vivo pharmacokinetics was found to be an efficacious inhibitor of 11beta-HSD1 in a rat pharmacodynamic model (ED(50)=10mg/kg).
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Animales , Benzamidas/farmacología , Relación Dosis-Respuesta a Droga , Células HeLa , Humanos , Macaca fascicularis , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Benzamidas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microsomas/metabolismo , Modelos Químicos , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Receptores de Esteroides/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Humanos , Cinética , Macaca fascicularis , Masculino , Modelos Moleculares , Conformación Molecular , Receptor X de Pregnano , Distribución TisularRESUMEN
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes the NADPH dependent interconversion of inactive cortisone to active cortisol. Excess 11beta-HSD1 or cortisol leads to insulin resistance and metabolic syndrome in animal models and in humans. Inhibiting 11beta-HSD1 activity signifies a promising therapeutic strategy in the treatment of Type 2 diabetes and related diseases. Herein, we report two highly potent and selective small molecule inhibitors of human 11beta-HSD1. While compound 1, a sulfonamide, functions as a simple substrate competitive inhibitor, compound 2, a triazole, shows the kinetic profile of a mixed inhibitor. Co-crystal structures reveal that both compounds occupy the 11beta-HSD1 catalytic site, but present distinct molecular interactions with the protein. Strikingly, compound 2 interacts much closer to the cofactor NADP+ and likely modifies its binding. Together, the structural and kinetic analyses demonstrate two distinctive molecular inhibition mechanisms, providing valuable information for future inhibitor design.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Enfermedades Metabólicas/patología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Secuencia de Aminoácidos , Sitios de Unión , Bioensayo , Catálisis , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Humanos , Cinética , Enfermedades Metabólicas/enzimología , Datos de Secuencia Molecular , NADP/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Triazoles/química , Triazoles/farmacologíaRESUMEN
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/administración & dosificación , Benzamidas/síntesis química , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Benzamidas/química , Benzamidas/metabolismo , Línea Celular , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Macaca fascicularis , Modelos Animales , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11beta-Hydroxysteroid Dehydrogenase Type 1 (11beta-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11beta-HSD1 IC(50)=3nM).