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1.
Bioorg Med Chem Lett ; 23(6): 1779-85, 2013 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-23414845

RESUMEN

In order to develop potent and selective focal adhesion kinase (FAK) inhibitors, synthetic studies on pyrazolo[4,3-c][2,1]benzothiazines targeted for the FAK allosteric site were carried out. Based on the X-ray structural analysis of the co-crystal of the lead compound, 8-(4-ethylphenyl)-5-methyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazine 4,4-dioxide 1 with FAK, we designed and prepared 1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin derivatives which selectively inhibited kinase activity of FAK without affecting seven other kinases. The optimized compound, N-(4-tert-butylbenzyl)-1,5-dimethyl-1,5-dihydropyrazolo[4,3-c][2,1]benzothiazin-8-amine 4,4-dioxide 30 possessed significant FAK kinase inhibitory activities both in cell-free (IC50=0.64µM) and in cellular assays (IC50=7.1µM). These results clearly demonstrated a potential of FAK allosteric inhibitors as antitumor agents.


Asunto(s)
Antineoplásicos/química , Óxidos S-Cíclicos/química , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Compuestos Heterocíclicos con 3 Anillos/química , Inhibidores de Proteínas Quinasas/química , Tiazinas/química , Sitio Alostérico , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/metabolismo , Evaluación Preclínica de Medicamentos , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/metabolismo , Simulación del Acoplamiento Molecular , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Relación Estructura-Actividad , Tiazinas/síntesis química , Tiazinas/metabolismo
2.
J Med Chem ; 53(1): 147-54, 2010 Jan 14.
Artículo en Inglés | MEDLINE | ID: mdl-19919106

RESUMEN

The synthesis of 5-chloro-, 6-chloro-, and 8-chloro-substituted 3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides is described. Their inhibitory effect on the insulin releasing process and their vasorelaxant activity was compared to that of previously reported 7-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides. "5-Chloro" compounds were found to be essentially inactive on both the insulin-secreting and the smooth muscle cells. By contrast, "8-chloro" and "6-chloro" compounds were found to be active on insulin-secreting cells, with the "6-chloro" derivatives emerging as the most potent drugs. Moreover, the "6-chloro" analogues exhibited less myorelaxant activity than their "7-chloro" counterparts. 8-Chloro-3-isopropylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (25b) and 6-chloro-3-cyclobutylamino-4H-1,2,4-benzothiadiazine 1,1-dioxide (19e) were further identified as K(ATP) channel openers by radioisotopic measurements conducted on insulin-secreting cells. Likewise, current recordings on HEK293 cells expressing human SUR1/Kir6.2 channels confirmed the highly potent activity of 19e (EC(50) = 80 nM) on such types of K(ATP) channels. The present work indicates that 6-chloro-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides appear to be more attractive than their previously described 7-chloro-substituted analogues as original drugs activating the SUR1/Kir6.2 K(ATP) channels.


Asunto(s)
Benzotiadiazinas/farmacología , Cloro/química , Óxidos S-Cíclicos/farmacología , Diazóxido/análogos & derivados , Diazóxido/farmacología , Islotes Pancreáticos/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Benzotiadiazinas/síntesis química , Benzotiadiazinas/química , Línea Celular , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/química , Diazóxido/química , Evaluación Preclínica de Medicamentos , Glucosa/farmacología , Humanos , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Estructura Molecular , Músculo Liso Vascular/metabolismo , Canales de Potasio/metabolismo , Ratas , Estereoisomerismo
3.
Bioorg Med Chem ; 16(17): 8127-35, 2008 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-18701300

RESUMEN

The synthesis of a series of new isothiazol-3(2H)-one 1,1-dioxides with halogenated (mostly fluorinated) pyridinyl and pentafluorophenyl substituents at 2-position is reported. These compounds (18-24) became easily accessible from 2-thiocyanato-1-carboxaldehydes and aminopyridines, pentafluoroaniline, respectively, by an isothiazolium cyclization-oxidation route. Compound 21 exhibited an IC(50) value of 3.1 microM toward human leukocyte elastase. The proteases cathepsin G, trypsin, cathepsin L, and angiotensin-converting enzyme, and the serine esterases acetylcholinesterase and cholesterol esterase were not inhibited by 21.


Asunto(s)
Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Elastasa de Leucocito/antagonistas & inhibidores , Acetilcolinesterasa/efectos de los fármacos , Catepsina G , Catepsina L , Catepsinas/antagonistas & inhibidores , Cristalografía por Rayos X , Óxidos S-Cíclicos/química , Ciclización , Cisteína Endopeptidasas , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Peptidil-Dipeptidasa A/efectos de los fármacos , Serina Endopeptidasas , Estereoisomerismo , Esterol Esterasa/antagonistas & inhibidores , Relación Estructura-Actividad , Tripsina/efectos de los fármacos
4.
J Med Chem ; 43(10): 2040-8, 2000 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-10821716

RESUMEN

Various 1,2-isothiazolidine-1,1-dioxide (gamma-sultam) derivatives containing an antioxidant moiety, 2,6-di-tert-butylphenol substituent, were prepared. Some compounds, which have a lower alkyl group at the 2-position of the gamma-sultam skeleton, showed potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), as well as production of interleukin (IL)-1 in in vitro assays. They also proved to be effective in several animal arthritic models without any ulcerogenic activities. Among these compounds, (E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1, 2-isothiazolidine-1,1-dioxide (S-2474) was selected as an antiarthritic drug candidate and is now under clinical trials. The structure-activity relationships (SAR) examined and some pharmacological evaluations are described.


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Artritis/tratamiento farmacológico , Óxidos S-Cíclicos/síntesis química , Isoenzimas/farmacología , Inhibidores de la Lipooxigenasa , Prostaglandina-Endoperóxido Sintasas/farmacología , Tiazoles/síntesis química , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Óxidos S-Cíclicos/efectos adversos , Óxidos S-Cíclicos/uso terapéutico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/uso terapéutico , Dinoprostona/antagonistas & inhibidores , Dinoprostona/biosíntesis , Edema/inducido químicamente , Edema/tratamiento farmacológico , Femenino , Mucosa Gástrica/efectos de los fármacos , Humanos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/farmacología , Leucotrieno B4/antagonistas & inhibidores , Leucotrieno B4/biosíntesis , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/uso terapéutico , Masculino , Proteínas de la Membrana , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Tiazoles/efectos adversos , Tiazoles/uso terapéutico
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