RESUMEN
We previously reported that compound 1, having a similar conformation to PTK787 (2) by forming a pseudo ring structure with an intramolecular non-bonded S-O interaction, exhibited a potent inhibitory activity against VEGFR2 tyrosine kinase (KDR). Applying the ideas of pseudo ring formations, we have designed three types of novel indole carboxamide derivatives 5-7 with an intramolecular hydrogen bonding or non-bonded S-O interaction. We describe the design and synthesis of 5-7, and also discuss the relationships of their KDR inhibitory activity and conformations that were stabilized by their intramolecular non-bonded interactions.
Asunto(s)
Inhibidores Enzimáticos/química , Indoles/química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Modelos Moleculares , Estructura MolecularRESUMEN
Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD).
Asunto(s)
Inhibidores de la Angiogénesis/química , Piridinas/química , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Artritis Reumatoide/tratamiento farmacológico , Células Cultivadas , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Trasplante Heterólogo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Optimization from compound 4a, having intramolecular S-O nonbonded interaction, led to discover compounds 4m and 4n. They were highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, AMD).
Asunto(s)
Anilidas/química , Piridinas/química , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Anilidas/síntesis química , Anilidas/uso terapéutico , Animales , Artritis Experimental/tratamiento farmacológico , Línea Celular , Neovascularización Coroidal/tratamiento farmacológico , Modelos Animales de Enfermedad , Células Endoteliales/citología , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Piridinas/síntesis química , Piridinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Factor A de Crecimiento Endotelial Vascular/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A three substituted urea derivative, SA13353 (compound 1a), exhibited potent inhibitory activity against lipopolysaccharide (LPS)-induced TNF-alpha production. We focused on the 1,1-substituted moiety (R(1) and R(2)) of SA13353 and investigated substituent effects of this moiety on LPS-induced TNF-alpha production by oral administration in rats. The synthesis of the urea derivatives was performed rapidly in a one-pot manner using a manual synthesizer. Several compounds containing hydrophobic substituents at this moiety showed more potent inhibitory activities than SA13353.
Asunto(s)
Factor de Necrosis Tumoral alfa/biosíntesis , Urea/análogos & derivados , Administración Oral , Animales , Piridinas/farmacología , Ratas , Ácidos Sulfénicos/química , Urea/síntesis química , Urea/farmacologíaRESUMEN
We designed and synthesized a novel 1,4-benzoxazin-3-one derivative 4 which would have inhibitory activities against tyrosine kinases. They could be synthesized easily from various carboxylic acids 10 and commercially available amines using TFP resin without purification. In this article, we will report the design and synthesis of a novel 1,4-benzoxazin-3-one chemical library 4 and the inhibitory activities against KDR and ABL which are closely related to chronic diseases such as cancer.
Asunto(s)
Benzoxazinas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Aminas , Benzoxazinas/farmacología , Ácidos Carboxílicos , Diseño de Fármacos , Proteínas Proto-Oncogénicas c-abl/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
We studied synthetic modifications of N-mercaptoacylamino acid derivatives to develop a new class of leukotriene A(4) (LTA(4)) hydrolase inhibitors. S-(4-Dimethylamino)benzyl-l-cysteine derivative 2a (SA6541) showed inhibitory activity against LTA(4) hydrolase (IC(50), 270nM) and selectivity over other metallopeptidases except angiotensin-converting enzyme (ACE, IC(50), 520nM). Modification at the para-substituent of the phenyl ring of compound 2a improved LTA(4) hydrolase inhibitory activity as well as selectivity over ACE. Finally, we obtained S-(4-cyclohexyl)benzy-l-cysteine derivatives 11l and 16i as potent and selective LTA(4) hydrolase inhibitors.
Asunto(s)
Cisteína/química , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos de Sulfhidrilo/síntesis química , Compuestos de Sulfhidrilo/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Evaluación Preclínica de Medicamentos , Modelos Moleculares , Relación Estructura-Actividad Cuantitativa , Compuestos de Sulfhidrilo/químicaRESUMEN
We studied the synthetic modification of structurally similar N-mercaptoacyl-L-proline and (4R)-N-mercaptoacylthiazolidine-4-carboxylic acid to obtain potent leukotriene A(4) (LTA(4)) hydrolase inhibitors. An N-mercaptoacyl group, (2S)-3-mercapto-2-methylpropionyl group, was effective for both scaffolds. Additional introduction of a large substituent such as 4-isopropylbenzylthio (3f), 4-tert-butylbenzylthio (3l) or 4-cyclohexylbenzylthio group (3m) with (S)-configuration at the C(4) position of proline yielded much more potent LTA(4) hydrolase inhibitors (IC(50); 52, 31, and 34 nM, respectively) than captopril (IC(50); 630,000 nM).
Asunto(s)
Ácidos Carboxílicos/síntesis química , Epóxido Hidrolasas/antagonistas & inhibidores , Prolina/análogos & derivados , Prolina/síntesis química , Compuestos de Sulfhidrilo/farmacología , Tiazolidinas/farmacología , Animales , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Leucotrieno A4/metabolismo , Modelos Químicos , Prolina/química , Prolina/farmacología , Relación Estructura-ActividadRESUMEN
We found 4-pyridylmethylthio derivative 1 to be very effective in using antiangiogenesis activity to prevent proliferation of HUVECs (Human Umbilical Vein Endothelial Cells), which was induced by vascular endothelial growth factor (VEGF). Compound 1 was equally effective in inhibiting VEGF receptor2 tyrosine kinase (KDR, IC(50)=26nM). We deduced that the inhibition was the result of binding the catalytic domain of VEGF receptor2 tyrosine kinase in a similar fashion to both phthalazine derivative PTK787 2 and anthranylamide derivative AAL993 3. In this report, we will describe the conformational analyses, from ab initio MO calculation and X-ray crystallographic analyses, of compound 1 and the analogs, which include non-active 9, all in comparison with 2 and 3. The conformation-activity relationships suggest that a nonbonded intramolecular interaction between the sulfur and the carbonyl oxygen of 1 was very important in inhibiting KDR.