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1.
Bioorg Med Chem Lett ; 22(24): 7486-9, 2012 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-23122816

RESUMEN

We conducted a high throughput screening for glyoxalase I (GLO1) inhibitors and identified 4,6-diphenyl-N-hydroxypyridone as a lead compound. Using a binding model of the lead and public X-ray coordinates of GLO1 enzymes complexed with glutathione analogues, we designed 4-(7-azaindole)-substituted 6-phenyl-N-hydroxypyridones. 7-Azaindole's 7-nitrogen was expected to interact with a water network, resulting in an interaction with the protein. We validated this inhibitor design by comparing its structure-activity relationship (SAR) with that of corresponding indole derivatives, by analyzing the binding mode with X-ray crystallography and by evaluating its thermodynamic binding parameters.


Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Indoles/química , Lactoilglutatión Liasa/antagonistas & inhibidores , Piridonas/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Lactoilglutatión Liasa/metabolismo , Modelos Moleculares , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Relación Estructura-Actividad
2.
J Med Chem ; 55(17): 7828-40, 2012 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-22889351

RESUMEN

Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.


Asunto(s)
Compuestos de Bencidrilo/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/uso terapéutico , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Compuestos de Bencidrilo/química , Compuestos de Bencidrilo/farmacocinética , Glucósidos/química , Glucósidos/farmacocinética , Humanos , Macaca fascicularis , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Transportador 2 de Sodio-Glucosa , Espectrometría de Masa por Ionización de Electrospray
3.
Bioorg Med Chem ; 20(13): 4117-27, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22652255

RESUMEN

C-Aryl 5a-carba-ß-d-glucopyranose derivatives were synthesized and evaluated for inhibition activity against hSGLT1 and hSGLT2. Modifications to the substituents on the two benzene rings resulted in enhanced hSGLT2 inhibition activity and extremely high hSGLT2 selectivity versus SGLT1. Using the created superimposed model, the reason for the high hSGLT2 selectivity was speculated to be that additional substituents occupied a new space, in a different way than known inhibitors. Among the tested compounds, the ethoxy compound 5h with high hSGLT2 selectivity exhibited more potent and longer hypoglycemic action in db/db mice than our O-carbasugar compound (1) and sergliflozin (2), which could be explained by its improved PK profiles relative to those of the two compounds. These results indicated that 5h might be a promising drug candidate for the treatment of type 2 diabetes.


Asunto(s)
Ciclohexanoles/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/análogos & derivados , Hipoglucemiantes/química , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Administración Oral , Animales , Área Bajo la Curva , Glucemia/análisis , Ciclohexanoles/farmacocinética , Ciclohexanoles/uso terapéutico , Glucosa/farmacocinética , Glucosa/uso terapéutico , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Obesos , Transportador 2 de Sodio-Glucosa/metabolismo , Relación Estructura-Actividad
4.
J Pharmacol Exp Ther ; 341(3): 692-701, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22410641

RESUMEN

Sodium/glucose cotransporter 2 (SGLT2) is the predominant mediator of renal glucose reabsorption and is an emerging molecular target for the treatment of diabetes. We identified a novel potent and selective SGLT2 inhibitor, tofogliflozin (CSG452), and examined its efficacy and pharmacological properties as an antidiabetic drug. Tofogliflozin competitively inhibited SGLT2 in cells overexpressing SGLT2, and K(i) values for human, rat, and mouse SGLT2 inhibition were 2.9, 14.9, and 6.4 nM, respectively. The selectivity of tofogliflozin toward human SGLT2 versus human SGLT1, SGLT6, and sodium/myo-inositol transporter 1 was the highest among the tested SGLT2 inhibitors under clinical development. Furthermore, no interaction with tofogliflozin was observed in any of a battery of tests examining glucose-related physiological processes, such as glucose uptake, glucose oxidation, glycogen synthesis, hepatic glucose production, glucose-stimulated insulin secretion, and glucosidase reactions. A single oral gavage of tofogliflozin increased renal glucose clearance and lowered the blood glucose level in Zucker diabetic fatty rats. Tofogliflozin also improved postprandial glucose excursion in a meal tolerance test with GK rats. In db/db mice, 4-week tofogliflozin treatment reduced glycated hemoglobin and improved glucose tolerance in the oral glucose tolerance test 4 days after the final administration. No blood glucose reduction was observed in normoglycemic SD rats treated with tofogliflozin. These findings demonstrate that tofogliflozin inhibits SGLT2 in a specific manner, lowers blood glucose levels by increasing renal glucose clearance, and improves pathological conditions of type 2 diabetes with a low hypoglycemic potential.


Asunto(s)
Compuestos de Bencidrilo/farmacología , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/farmacología , Hemoglobina Glucada/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Diabetes Mellitus Tipo 2/sangre , Relación Dosis-Respuesta a Droga , Intolerancia a la Glucosa/tratamiento farmacológico , Prueba de Tolerancia a la Glucosa , Humanos , Hiperglucemia/sangre , Hiperglucemia/tratamiento farmacológico , Riñón/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos , Ratas , Ratas Sprague-Dawley , Ratas Zucker
5.
Bioorg Med Chem ; 20(3): 1271-80, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22225917

RESUMEN

Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Haplorrinos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Sprague-Dawley , Proteínas Tirosina Quinasas Receptoras/metabolismo
6.
J Med Chem ; 54(18): 6286-94, 2011 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-21823617

RESUMEN

9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.


Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Piperazinas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Carbazoles/farmacocinética , Carbazoles/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Técnicas In Vitro , Macaca fascicularis , Masculino , Ratones , Ratones SCID , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Trasplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacología , Relación Estructura-Actividad , Trasplante Heterólogo
7.
Bioorg Med Chem ; 19(18): 5334-41, 2011 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-21873071

RESUMEN

5a-Carba-ß-D-glucopyranose derivatives were synthesized and identified as novel SGLT2-selective inhibitors. These inhibitors exhibited potent SGLT2 inhibition with high selectivity over SGLT1. Among the tested compounds, 6f indicated the most potent hSGLT2 inhibition and the highest selectivity over hSGLT1. Moreover, the pharmacokinetics data also showed that 6h, which had the same aglycon structure as sergliflozin-active (3-active), had a threefold longer half-life time (T(1/2)) than sergliflozin (3) with a high distribution volume in db/db mice. Subsequently, 6h lowered blood glucose levels as much as 3 and showed longer hypoglycemic action than 3 in db/db mice.


Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/análogos & derivados , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucosa/síntesis química , Glucosa/química , Glucosa/farmacología , Masculino , Ratones , Ratones Obesos , Conformación Molecular , Datos de Secuencia Molecular , Transportador 2 de Sodio-Glucosa/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Distribución Tisular
8.
Bioorg Med Chem ; 19(16): 4721-9, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-21795053

RESUMEN

Novel vitamin D(3) analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3ß-hydroxy group of 1α,25-dihydroxyvitamin D(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.


Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Colecalciferol/análogos & derivados , Osteoporosis/tratamiento farmacológico , Animales , Densidad Ósea/efectos de los fármacos , Conservadores de la Densidad Ósea/química , Conservadores de la Densidad Ósea/farmacología , Calcitriol/análogos & derivados , Calcitriol/química , Calcitriol/farmacología , Calcio/sangre , Línea Celular , Colecalciferol/farmacología , Colecalciferol/uso terapéutico , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Ratones , Osteocalcina/análisis , Osteocalcina/fisiología , Osteoporosis/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/efectos de los fármacos , Receptores de Calcitriol/genética , Esteroides/química , Relación Estructura-Actividad
9.
Cancer Cell ; 19(5): 679-90, 2011 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-21575866

RESUMEN

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.


Asunto(s)
Antineoplásicos/farmacología , Carbazoles/farmacología , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Administración Oral , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Carbazoles/administración & dosificación , Carbazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/genética , Humanos , Ratones , Ratones Desnudos , Ratones SCID , Modelos Moleculares , Mutación , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Piperidinas/administración & dosificación , Piperidinas/química , Conformación Proteica , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Proteínas Tirosina Quinasas Receptoras/química , Proteínas Tirosina Quinasas Receptoras/genética , Proteínas Tirosina Quinasas Receptoras/metabolismo , Proteínas Recombinantes de Fusión/antagonistas & inhibidores , Proteínas Recombinantes de Fusión/metabolismo , Factores de Tiempo , Transfección , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
10.
Bioorg Med Chem ; 14(6): 1838-50, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16307885

RESUMEN

A series of 16-en-22-oxa-derivatives of vitamin D3 based on the structure of maxacalcitol (2) were prepared. Maxacalcitol is currently used topically for the treatment of psoriasis and is recognized as the most successful antedrug of natural vitamin D(3) because it retains the original antiproliferative activity of calcitriol without increased calcemic activity. We introduced 16-olefinic functionality to accelerate the oxidative metabolism of the drug in liver, presumed to be essential for the reduction of calcemic activity, and modified the side-chain moiety by placing the 22-oxygen on the more labile allylic carbon center. Novel 22-oxa analogs (7a-i), carrying either the 24-alkynyl bond or 24-hydroxy functionality in addition to the 16-double bond were synthesized and their pharmacokinetics were evaluated.


Asunto(s)
Psoriasis , Vitamina D/análogos & derivados , Vitamina D/química , Animales , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Evaluación Preclínica de Medicamentos , Células Epidérmicas , Epidermis/efectos de los fármacos , Humanos , Queratinocitos/efectos de los fármacos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Psoriasis/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Vitamina D/farmacocinética
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