RESUMO
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.
Assuntos
Inibidores Enzimáticos/química , Indóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Indóis/farmacologia , Modelos Moleculares , Estrutura MolecularRESUMO
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).
Assuntos
Inibidores da Angiogênese/química , Piridinas/química , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/uso terapêutico , Animais , Artrite Reumatoide/tratamento farmacológico , Células Cultivadas , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
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).
Assuntos
Anilidas/química , Piridinas/química , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Anilidas/síntese química , Anilidas/uso terapêutico , Animais , Artrite Experimental/tratamento farmacológico , Linhagem Celular , Neovascularização de Coroide/tratamento farmacológico , Modelos Animais de Doenças , Células Endoteliais/citologia , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Piridinas/síntese química , Piridinas/uso terapêutico , Ratos , Relação Estrutura-Atividade , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Fator de Necrose Tumoral alfa/biossíntese , Ureia/análogos & derivados , Administração Oral , Animais , Piridinas/farmacologia , Ratos , Ácidos Sulfênicos/química , Ureia/síntese química , Ureia/farmacologiaRESUMO
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.
Assuntos
Cisteína/química , Epóxido Hidrolases/antagonistas & inibidores , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Inibidores da Enzima Conversora de Angiotensina/síntese química , Inibidores da Enzima Conversora de Angiotensina/química , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Avaliação Pré-Clínica de Medicamentos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Compostos de Sulfidrila/químicaRESUMO
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.
Assuntos
Benzoxazinas/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Aminas , Benzoxazinas/farmacologia , Ácidos Carboxílicos , Desenho de Fármacos , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
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).
Assuntos
Ácidos Carboxílicos/síntese química , Epóxido Hidrolases/antagonistas & inibidores , Prolina/análogos & derivados , Prolina/síntese química , Compostos de Sulfidrila/farmacologia , Tiazolidinas/farmacologia , Animais , Ácidos Carboxílicos/química , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Leucotrieno A4/metabolismo , Modelos Químicos , Prolina/química , Prolina/farmacologia , Relação Estrutura-AtividadeRESUMO
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.