RESUMO
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Assuntos
Amidas/síntese química , Aminopiridinas/síntese química , Anticoagulantes/síntese química , Inibidores do Fator Xa , Tiofenos/síntese química , ortoaminobenzoatos/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Cristalografia por Raios X , Cães , Humanos , Técnicas In Vitro , Masculino , Modelos Moleculares , Tempo de Protrombina , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Trombose Venosa/tratamento farmacológico , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/farmacologiaRESUMO
Heat-shock protein-90 is an attractive target for anticancer drugs, as heat-shock protein-90 blockers such as the ansamycin 17-(allylamino)-17-demethoxygeldanamycin greatly reduce the expression of many signaling molecules that are disregulated in cancer cells and are key drivers of tumor growth and metastasis. While 17-(allylamino)-17-demethoxygeldanamycin has shown promise in clinical trials, this compound class has significant template-related drawbacks. In this paper, we describe a new, potent non-ansamycin small-molecule inhibitor of heat-shock protein-90, BX-2819, containing resorcinol and triazolothione rings. Structural studies demonstrate binding of BX-2819 to the ADP/ATP-binding pocket of heat-shock protein-90. The compound blocked expression of heat-shock protein-90 client proteins in cancer cell lines and inhibited cell growth with a potency similar to 17-(allylamino)-17-demethoxygeldanamycin. In a panel of four cancer cell lines, BX-2819 blocked growth with an average IC(50) value of 32 nM (range of 7-72 nM). Efficacy studies demonstrated that treatment with BX-2819 significantly inhibited the growth of NCI-N87 and HT-29 tumors in nude mice, consistent with pharmacodynamic studies showing inhibition of heat-shock protein-90 client protein expression in tumors for greater than 16 h after dosing. These data support further studies to assess the potential of BX-2819 and related analogs for the treatment of cancer.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Triazóis/farmacologia , Animais , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Células HT29 , Humanos , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Camundongos , Camundongos Nus , Transplante Heterólogo , Triazóis/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
Assuntos
Fármacos Anti-HIV/química , Anti-Inflamatórios não Esteroides/química , Antagonistas dos Receptores CCR5 , Mitoguazona/análogos & derivados , Fármacos Anti-HIV/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Células Cultivadas , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Relação Estrutura-AtividadeRESUMO
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Desenho de Fármacos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese químicaRESUMO
Based on the lead compound BX-517, a series of C-4' substituted indolinones have been synthesized and evaluated for PDK1 inhibition. Modification at C-4' of the pyrrole afforded potent compounds (7b and 7d) with improved solubility and ADME properties. In this letter, we describe the synthesis, selectivity profile, and pharmacokinetic data of selected compounds.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Ureia/análogos & derivados , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Linhagem Celular Tumoral , Humanos , Indóis/farmacologia , Inibidores de Proteínas Quinases/química , Ureia/química , Ureia/farmacologiaRESUMO
The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Feminino , Células HeLa , Humanos , Técnicas In Vitro , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Melanoma Experimental/secundário , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Pirimidinas/química , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.