RESUMEN
Starting from screening hit, (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7), we optimized the potency and pharmacokinetic properties. This led to the identification of compounds with good in vivo activity in a mouse pharmacodynamic model of inhibition of 11ßHSD1.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Alcanfor/química , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Pirazolonas/síntesis química , Pirazolonas/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Animales , Activación Enzimática/efectos de los fármacos , Femenino , Hidrocortisona/sangre , Concentración 50 Inhibidora , Ratones , Estructura Molecular , RatasRESUMEN
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase ß-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
Asunto(s)
Bencenoacetamidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Activadores de Enzimas/síntesis química , Glucoquinasa/metabolismo , Hipoglucemiantes/síntesis química , Animales , Bencenoacetamidas/farmacocinética , Bencenoacetamidas/farmacología , Perros , Activadores de Enzimas/farmacocinética , Activadores de Enzimas/farmacología , Femenino , Glucosa/metabolismo , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Lipidosis/metabolismo , Hígado/metabolismo , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Periodo Posprandial , Conejos , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
7-N-Acetamide-4-methoxy-2-aminobenzothiazole 4-fluorobenzamide (compound 1) was chosen as a drug-like and non-xanthine based starting point for the discovery of A(2B) receptor antagonists because of its slight selectivity against A(1) and A(2A) receptors and modest A(2B) potency. SAR exploration of compound 1 described herein included modifications to the 7-N-acetamide group, substitution of the 4-methoxy group by halogens as well as replacement of the p-flouro-benzamide side chain. This work culminated in the identification of compound 37 with excellent A(2B) potency, modest selectivity versus A(2A) and A(1) receptors, and good rodent PK properties.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Benzotiazoles/farmacología , Receptor de Adenosina A2B/metabolismo , Xantina/química , Antagonistas del Receptor de Adenosina A2/química , Benzotiazoles/química , Relación Estructura-ActividadRESUMEN
Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SAR development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucoquinasa/efectos de los fármacos , Hipoglucemiantes/química , Sulfonas/farmacología , Tiazoles/farmacología , Animales , Glucemia , Línea Celular , Citotoxinas , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Humanos , Insulina , Masculino , Ratones , Farmacocinética , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/toxicidad , Tiazoles/química , Tiazoles/toxicidadRESUMEN
Two libraries of hMC4R agonists, X-Y-DPhe(7)-Arg(8)-2-Nal(9)-Z-NH(2) and X-Y-DPhe(7)-Arg(8)-Trp(9)-Z-NH(2), totaling 185 peptides were prepared using Irori radiofrequency tagging technology and Argonaut Quest 210 Synthesizer, where X stands for N-caps, Y for His(6) surrogates and Z for Gly(10) surrogates. As a result of this study, His-modified pentapeptides with Trp were found to be more hMC4R potent than the corresponding 2-Nal analogs, novel N-caps and Gly surrogates were identified and 19 new peptides which are potent hMC4R agonists (EC(50) 1-15nM) and selective against hMC1R were discovered.
Asunto(s)
Oligopéptidos/síntesis química , Biblioteca de Péptidos , Receptor de Melanocortina Tipo 4/agonistas , Secuencia de Aminoácidos , Glicina , Humanos , Oligopéptidos/química , Oligopéptidos/farmacología , Relación Estructura-ActividadRESUMEN
Linear pentapeptides (Penta-cis-Apc-DPhe-Arg-Trp-Gly-NH2) containing 1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc) and substituted Apc are potent hMC4R agonists and they are inactive or weakly active in hMC1R, hMC3R, and hMC5R agonist assays. This study, together with our earlier report on 5-BrAtc, demonstrated the importance of replacing His6 with phenyl-containing rigid templates in achieving good hMC4R agonist potency and selectivity against hMC1R in linear pentapeptides.
Asunto(s)
Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ciclohexanos/química , Ciclohexanos/farmacología , Receptor de Melanocortina Tipo 1/agonistas , Receptor de Melanocortina Tipo 4/agonistas , Secuencia de Aminoácidos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Sensibilidad y Especificidad , Especificidad por SustratoRESUMEN
A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.
Asunto(s)
Diaminas/farmacología , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/farmacología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Triazinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Glucemia/efectos de los fármacos , Diaminas/síntesis química , Diaminas/farmacocinética , Modelos Animales de Enfermedad , Ditiotreitol/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Concentración 50 Inhibidora , Inyecciones Intravenosas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacocinéticaRESUMEN
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
Asunto(s)
Proteínas Portadoras , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucoquinasa/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Hígado/efectos de los fármacos , Tiazoles/farmacología , Proteínas Adaptadoras Transductoras de Señales , Regulación Alostérica , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Activación Enzimática , Activadores de Enzimas/química , Activadores de Enzimas/farmacología , Prueba de Tolerancia a la Glucosa , Homeostasis , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Insulina/sangre , Secreción de Insulina , Péptidos y Proteínas de Señalización Intracelular , Islotes Pancreáticos/metabolismo , Cetoácidos/metabolismo , Hígado/metabolismo , Glucógeno Hepático/biosíntesis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Proteínas/metabolismo , Proteínas/farmacología , Ratas , Ratas Wistar , Proteínas Recombinantes/metabolismo , Estereoisomerismo , Tiazoles/químicaRESUMEN
A series of MT-II related cyclic peptides, based on potent but non-selective hMC4R agonist (Penta-c[Asp-His(6)-DPhe(7)-Arg(8)-Trp(9)-Lys]-NH(2)) was prepared in which His(6) residue was systematically substituted. Two of the most interesting peptides identified in this study are Penta-c[Asp-5-ClAtc-DPhe-Arg-Trp-Lys]-NH(2) and Penta-c[Asp-5-ClAtc-DPhe-Cit-Trp-Lys]-NH(2) which are potent hMC4R agonists and are either inactive or weak partial agonists (not tested for their antagonist activities) in hMC1R, hMC3R and hMC5R agonist assays.
Asunto(s)
Histidina/química , Receptores de Corticotropina/agonistas , Sustitución de Aminoácidos , Supervivencia Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Receptor de Melanocortina Tipo 4 , Receptores de Melanocortina , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Systematic substitution of His(6) residue using non-selective hMC4R pentapeptide agonist (Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2)) as the template led to the identification of Bu-Atc(6)(2-aminotetraline-2-carboxylic acid)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which showed moderate selectivity towards hMC4R over hMC1R. Further SAR studies resulted in the discovery of Penta-5-BrAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) and Penta-5-Me(2)NAtc(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) which are potent hMC4R agonists and are inactive in hMC1R, hMC3R and hMC5R agonist assays.
Asunto(s)
Oligopéptidos/síntesis química , Receptores de Corticotropina/agonistas , Secuencia de Aminoácidos , Sustitución de Aminoácidos , AMP Cíclico/biosíntesis , Histidina , Humanos , Oligopéptidos/metabolismo , Oligopéptidos/farmacología , Unión Proteica , Receptor de Melanocortina Tipo 4 , Receptores de Corticotropina/metabolismo , Receptores de Melanocortina , Relación Estructura-ActividadRESUMEN
A series of pentapeptides, based on Bu-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-NH(2) and modified at the Arg(8) position, was prepared and pharmacologically characterized. Peptides containing either cyanoguanidine or acylguanidine, two substantially less basic arginine surrogates, were found to retain the agonist activity of the parent peptide at both hMC1R and hMC4R. This study unequivocally shows that the positive charge of Arg(8) is not essential for efficient interactions of our pentapeptide with both hMC1R and hMC4R.
Asunto(s)
Oligopéptidos/síntesis química , Receptores de Corticotropina/agonistas , Sustitución de Aminoácidos , Arginina , Sitios de Unión , Guanidinas , Humanos , Oligopéptidos/farmacología , Unión Proteica , Receptor de Melanocortina Tipo 4 , Receptores de Melanocortina , Relación Estructura-ActividadRESUMEN
The cyclodimerization of p-toluenesulfonamide and 3-chloro-2-(chloromethyl)-1-propene to prepare N,N'-bis(p-toluenesulfonyl)-3,7-bis(methylene)-1,5-diazacyclooctane (1a) and its ozonation to the corresponding 3,7-dione 2a are reported. Unusual transannular cyclizations initiated by lithium aluminum hydride treatment or bromination of 1a and oxidative coupling of the dioxime derived from 2a are described. These reactions lead, respectively, to the following derivatives of the little-studied 3,7-diazabicyclo[3.3.0]octane ring system: 1,5-dimethyl-3,7-diazabicyclo[3.3.0]octane (5), N,N'-bis(p-toluenesulfonyl)-1,5-bis(bromomethyl)-3,7-diazabicyclo[3.3.0]octane (8), and N,N'-bis(p-toluenesulfonyl)-1,5-dinitro-3,7-diazabicyclo[3.3.0]octane, (12). Acid-catalyzed hydration of 1a, in contrast, gives the expected 5-methyl-3,7-diazabicyclo[3.3.1]nonan-1-ol (10). Reaction of the dibromide 8 with the nucleophiles, sodium sulfide, sodium oxide, and sodium p-toluenesulfonamide conveniently delivers the corresponding novel 3,7,10-triheterocyclic [3.3.3]propellanes.