RESUMO
In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.
RESUMO
Derivatives of (1,2,3-triazol-4-yl)benzenamines are described as potent and ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 and VEGFR-1 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays.
Assuntos
Derivados de Benzeno/síntese química , Derivados de Benzeno/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sítios de Ligação/efeitos dos fármacos , Humanos , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Novel derivatives of isothiazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds exhibited VEGFR-2 inhibitory activity comparable to that of Vatalanib in both HTRF enzymatic and cellular assays. Several derivatives featuring bulky meta-substituents in the amide portion of the molecule displayed 4- to 8-fold specificity for VEGFR-2 versus VEGFR-1. Active molecules also showed high intrinsic permeability (> 30 x 10(-5) cm/min) across Caco-2 cell monolayer.
Assuntos
Tiazóis/síntese química , Tiazóis/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Células CACO-2 , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Indóis/farmacologia , Estrutura Molecular , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Oligonucleotídeos , Ftalazinas/farmacologia , Piridinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A series of arylphthalazine derivatives were synthesized and evaluated as antagonists of VEGF receptor II (VEGFR-2). IM-094482 57, which was prepared in two steps from commercially available starting materials, was found to be a potent inhibitor of VEGFR-2 in enzymatic, cellular and mitogenic assays (comparable activity to ZD-6474). Additionally, 57 inhibited the related receptor, VEGF receptor I (VEGFR-1), and showed excellent exposure when dosed orally to female CD-1 mice.
Assuntos
Ftalazinas/farmacocinética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Feminino , Isoquinolinas/síntese química , Isoquinolinas/farmacocinética , Camundongos , Camundongos Endogâmicos , Ftalazinas/administração & dosagem , Ftalazinas/síntese química , Piperidinas , Quinazolinas , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
We have discovered novel inhibitors of VEGFR-2 kinase with low nanomolar potency in both enzymatic and cell-based assays. Active series are heteroaryl-ketone compounds containing a central aromatic ring with either an indazolyl or indolyl keto group in the ortho orientation to the benzylic amine group (Fig. 1). The best compounds were demonstrated to be inactive against a small select panel of tyrosine and serine/threonine kinases with the exception of VEGFR-1 kinase, a close family member. In addition, the lead candidate 8 displayed acceptable exposure levels when administered orally to mice.
Assuntos
Cetonas , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Administração Oral , Animais , Técnicas de Química Combinatória , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Camundongos , Estrutura Molecular , Piperidinas/farmacologia , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel derivatives of 1,2,4-triazoles are described as potent ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds display VEGFR-2 inhibitory activity comparable to that of Vatalanib and Vandetanib in both homogenous time-resolved fluorescence enzymatic and cellular assays. Several active molecules feature high intrinsic permeability (>30 x 10(-5) cm/min) across Caco-2 cell monolayer.
Assuntos
Compostos de Anilina/química , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazóis/farmacologia , Células Cultivadas , Humanos , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Triazóis/químicaRESUMO
We have developed a series of novel potent 1-(2-(pyridin-4-yl)ethyl)-1H-azole-5-carboxamides active against kinases VEGFR-2 and -1. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the 5-carboxamide substituent at the azole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100 nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanib(trade)) and ZD6474 (Vandetanib(trade mark)). High permeability of active compounds across the Caco-2 cell monolayer (>40 x 10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Assuntos
Amidas/química , Azóis/química , Química Farmacêutica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Proteínas Quinases/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Trifosfato de Adenosina/química , Azóis/farmacologia , Ligação Competitiva , Células CACO-2 , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ftalazinas/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/química , Piridinas/farmacologia , Quinazolinas/farmacologiaRESUMO
We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed > 10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis' PTK787 (Vatalanib). High permeability of active compounds across the Caco-2 cell monolayer (> 30x10(-5) cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Assuntos
Azóis/síntese química , Azóis/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Azóis/farmacocinética , Ligação Competitiva , Células CACO-2 , Permeabilidade da Membrana Celular , Humanos , Concentração Inibidora 50 , Absorção Intestinal , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
Novel potent derivatives of phthalazine are described as an adenosine triphosphate-competitive inhibitors of vascular endothelial growth factor receptors I and II. A number of compounds display vascular endothelial growth factor receptor II inhibitory activity reaching that of Vatalanib A (IC(50): < 50 nm) in an homogenous time-resolved fluorescence enzymatic assay.
Assuntos
Ftalazinas/química , Ftalazinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Sítios de Ligação , Ligação Competitiva , Humanos , Concentração Inibidora 50 , Ftalazinas/síntese química , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
Novel potent derivatives of phthalazine are described as ATP-competitive inhibitors of vascular endothelial growth factor receptors I and II (VEGFR-1/2). A number of compounds display VEGFR-2 inhibitory activity reaching that of Vatalanib 3 (IC50 < 100 nm) in an HTRF enzymatic assay. Several derivatives also show good potential for the development as VEGFR-2 specific inhibitors showing 15-20-fold selectivity over VEGFR-1.
Assuntos
Ftalazinas/química , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Trifosfato de Adenosina/química , Ligação Competitiva , Desenho de Fármacos , Humanos , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Novel tricyclic derivatives containing an oxazepine, thiazepine, or diazepine ring were studied for their EGFR tyrosine kinase inhibitory activity. While the oxazepines were in general more potent than thiazepines, the diazepines displayed somewhat different structure-activity relationships. Moreover, the diazepines, in contrast to the oxazepines, showed appreciable inhibitory activity against the KDR tyrosine kinase. Furthermore, both oxazepines and diazepines demonstrated significant ability to inhibit autophosphorylation of EGFR in DiFi cells (generally, IC(50) values in the single-digit micromolar to submicromolar range).
Assuntos
Antineoplásicos/síntese química , Azepinas/síntese química , Azepinas/farmacologia , Receptores ErbB/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Antineoplásicos/farmacologia , Azepinas/química , Linhagem Celular Tumoral , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Concentração Inibidora 50 , Proteínas de Neoplasias/antagonistas & inibidores , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Estrogen is a hormone critical in the development, normal physiology and pathophysiology of numerous human tissues. The effects of estrogen have traditionally been solely ascribed to estrogen receptor alpha (ERalpha) and more recently ERbeta, members of the soluble, nuclear ligand-activated family of transcription factors. We have recently shown that the seven-transmembrane G protein-coupled receptor GPR30 binds estrogen with high affinity and resides in the endoplasmic reticulum, where it activates multiple intracellular signaling pathways. To differentiate between the functions of ERalpha or ERbeta and GPR30, we used a combination of virtual and biomolecular screening to isolate compounds that selectively bind to GPR30. Here we describe the identification of the first GPR30-specific agonist, G-1 (1), capable of activating GPR30 in a complex environment of classical and new estrogen receptors. The development of compounds specific to estrogen receptor family members provides the opportunity to increase our understanding of these receptors and their contribution to estrogen biology.
Assuntos
Receptores Acoplados a Proteínas G/agonistas , Animais , Ligação Competitiva , Células COS , Cálcio/metabolismo , Movimento Celular , Chlorocebus aethiops , Bases de Dados como Assunto , Relação Dose-Resposta a Droga , Ativação Enzimática , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Humanos , Ligantes , Microscopia de Fluorescência , Modelos Biológicos , Modelos Moleculares , Fosfatidilinositol 3-Quinases/metabolismo , Ligação Proteica , Conformação Proteica , Receptores de Estrogênio/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
We have developed a series of novel potent ((pyridin-4-yl)ethyl)pyridine derivatives active against kinases VEGFR-1 and -2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase selectivity could be controlled by varying the arylamino substituent at the 1,3,4-oxadiazole ring. The most specific molecules displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in vitro and in cell-based assays (IC(50)<100nM) were similar to those of reported clinical and development candidates, including PTK787 (Vatalanibtrade mark). High permeability of active compounds across the Caco-2 cell monolayer (>30x10(-5)cm/min) is indicative of their potential for intestinal absorption upon oral administration.
Assuntos
Inibidores Enzimáticos/farmacologia , Piridinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Células CACO-2 , Humanos , Modelos MolecularesRESUMO
A novel class of 1-(isoquinolin-5-yl)-4-arylamino-phthalazines is described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Many compounds display VEGFR-2 inhibitory activity with an IC(50) as low as 0.017 microM in an HTRF enzymatic assay. The compounds also inhibit VEGFR-1, a related tyrosine kinase.
Assuntos
Isoquinolinas/farmacologia , Ftalazinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fluorimunoensaio , Humanos , Concentração Inibidora 50 , Isoquinolinas/síntese química , Ftalazinas/síntese química , Relação Estrutura-AtividadeRESUMO
A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
Assuntos
Azepinas/síntese química , Azepinas/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Trifosfato de Adenosina/metabolismo , Azepinas/química , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Estrutura Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A novel potent derivatives of hetaryl imidazoles were described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido functionality, both dual and specific VEGFR-2 thiazoles were identified.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Imidazóis/síntese química , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
A novel class of N-(4-{[4-(1H-benzoimidazol-2-yl)-arylamino]-methyl}-phenyl)-benzamides are described as inhibitors of the endo-beta-glucuronidase heparanase. Among them are N-(4-{[4-(1H-benzoimidazol-2-yl)-phenylamino]-methyl}-phenyl)-3-bromo-4-methoxy-benzamide (15h), and N-(4-{[5-(1H-benzoimidazol-2-yl)-pyridin-2-ylamino]-methyl}- phenyl)-3-bromo-4-methoxy-benzamide (23) which displayed good heparanase inhibitory activity (IC(50) 0.23-0.29 microM), with the latter showing oral exposure in mice.
Assuntos
Benzamidas/farmacologia , Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Glucuronidase/antagonistas & inibidores , Administração Oral , Animais , Benzamidas/administração & dosagem , Benzamidas/química , Benzimidazóis/administração & dosagem , Benzimidazóis/química , Configuração de Carboidratos , Sequência de Carboidratos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/química , Técnicas In Vitro , Camundongos , Modelos Animais , Dados de Sequência Molecular , Estrutura Molecular , Peso Molecular , Relação Estrutura-AtividadeRESUMO
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model.
Assuntos
Carbanilidas/farmacologia , Inibidores Enzimáticos/farmacologia , Glucuronidase/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Animais , Carbanilidas/síntese química , Carbanilidas/classificação , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/classificação , Técnicas In Vitro , Melanoma Experimental/secundário , Camundongos , Estrutura Molecular , Peso Molecular , Metástase Neoplásica/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Novel potent derivatives of N-(aryl)-4-(azolylethyl)thiazole-5-carboxamides are described as inhibitors of vascular endothelial growth factor receptor II (VEGFR-2). Several compounds display VEGFR-2 inhibitory activity reaching IC(50)<100 nM in both enzymatic and cellular assays. The compounds also inhibit the related tyrosine kinase, VEGFR-1. By controlling the substitution pattern on the 5-carboxamido pharmacophore, both dual and specific VEGFR-2 thiazoles were identified.
Assuntos
Inibidores Enzimáticos/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/química , Animais , Células CHO , Cricetinae , Concentração Inibidora 50 , Estrutura Molecular , Tiazóis/químicaRESUMO
Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.