RESUMO
We describe the synthesis of triazole-containing carboline derivatives and their utility as bromodomain and extra-terminal (BET) inhibitors. A convergent synthetic route permitted the detailed investigation of deuteration and fluorination strategies to reduce clearance while maintaining a favorable in vitro profile. This work led to the identification of a potent BET inhibitor, 2-{8-fluoro-3-[4-(2H3)methyl-1-methyl-1H-1,2,3-triazol-5-yl]-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol (15), which demonstrated reduced clearance and an improved pharmacokinetic (PK) profile across preclinical species. Importantly, no major metabolite was observed when 15 was incubated with human hepatocytes (hHEP) for 2 h. This study culminated with the evaluation of 15 in a mouse triple-negative breast cancer (TNBC) tumor model where it demonstrated robust efficacy at low doses.
RESUMO
Inhibition of the bromodomain and extra-terminal (BET) family of adaptor proteins is an attractive strategy for targeting transcriptional regulation of key oncogenes, such as c-MYC. Starting with the screening hit 1, a combination of structure-activity relationship and protein structure-guided drug design led to the discovery of a differently oriented carbazole 9 with favorable binding to the tryptophan, proline, and phenylalanine (WPF) shelf conserved in the BET family. Identification of an additional lipophilic pocket and functional group optimization to optimize pharmacokinetic (PK) properties culminated in the discovery of 18 (BMS-986158) with excellent potency in binding and functional assays. On the basis of its favorable PK profile and robust in vivo activity in a panel of hematologic and solid tumor models, BMS-986158 was selected as a candidate for clinical evaluation.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Descoberta de Drogas , Fenilalanina/farmacologia , Prolina/farmacologia , Triptofano/farmacologia , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbazóis/administração & dosagem , Carbazóis/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Fenilalanina/administração & dosagem , Fenilalanina/química , Prolina/administração & dosagem , Prolina/química , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Triptofano/administração & dosagem , Triptofano/químicaRESUMO
Structure-activity relationships in a series of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides identified highly potent inhibitors of γ-secretase mediated signaling of Notch1/2/3/4 receptors. On the basis of its robust in vivo efficacy at tolerated doses in Notch driven leukemia and solid tumor xenograft models, 12 (BMS-906024) was selected as a candidate for clinical evaluation.
RESUMO
This Letter describes synthesis, SAR, and biological activity of (2-oxo-1,4-benzodiazepin-3-yl)-succinamides as inhibitors of γ-secretase mediated signaling of Notch receptors. Optimization of this series led to the identification of BMS-871 (compound 30) which displayed robust in vivo efficacy in Notch-dependent leukemia and solid tumor xenograft models.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzodiazepinonas/administração & dosagem , Benzodiazepinonas/farmacologia , Receptores Notch/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/química , Benzodiazepinonas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Receptores Notch/metabolismo , Relação Estrutura-AtividadeRESUMO
PURPOSE: The extensive involvement of the HER kinases in epithelial cancer suggests that kinase inhibitors targeting this receptor family have the potential for broad spectrum antitumor activity. BMS-690514 potently inhibits all three HER kinases, and the VEGF receptor kinases. This report summarizes data from biochemical and cellular pharmacology studies, as well as antitumor activity of BMS-690514. EXPERIMENTAL DESIGN: The potency and selectivity of BMS-690514 was evaluated by using an extensive array of enzymatic and binding assays, as well as cellular assays that measure proliferation and receptor signaling. Antitumor activity was evaluated by using multiple xenograft models that depend on HER kinase signaling. The antiangiogenic properties of BMS-690514 were assessed in a matrigel plug assay, and effect on tumor blood flow was measured by dynamic contrast-enhanced MRI. RESULTS: BMS-690514 is a potent and selective inhibitor of epidermal growth factor receptor (EGFR), HER2, and HER4, as well as the VEGF receptor kinases. It inhibits proliferation of tumor cells with potency that correlates with inhibition of receptor signaling, and induces apoptosis in lung tumor cells that have an activating mutation in EGFR. Antitumor activity was observed with BMS-690514 at multiple doses that are well tolerated in mice. There was evidence of suppression of tumor angiogenesis and endothelial function by BMS-690514, which may contribute to its efficacy. CONCLUSIONS: By combining inhibition of two receptor kinase families, BMS-690524 is a novel targeted agent that disrupts signaling in the tumor and its vasculature.
Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Neoplasias/enzimologia , Piperidinas/farmacologia , Pirróis/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Triazinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/irrigação sanguínea , Neovascularização Patológica/enzimologia , Receptor ErbB-2/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of 5-((4-aminopiperidin-1-yl)methyl)-pyrrolo[2,1-f][1,2,4]triazin-4-amines with small aniline substituents at the C4 position were optimized for dual EGFR and HER2 protein tyrosine kinase inhibition. Compound 8l exhibited promising oral efficacy in both EGFR and HER2-driven human tumor xenograft models.
Assuntos
Antineoplásicos/química , Antineoplásicos/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Receptores ErbB/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Neoplasias/enzimologia , Proteínas Tirosina Quinases/farmacocinética , Proteínas Tirosina Quinases/farmacologia , Pirróis/química , Pirróis/farmacocinética , Pirróis/farmacologia , Pirróis/uso terapêutico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Triazinas/química , Triazinas/farmacocinética , Triazinas/farmacologia , Triazinas/uso terapêutico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Structure-activity relationships in a series of 4-[1H-indazol-5-ylamino]pyrrolo[2,1-f][1,2,4]triazine-6-carbamates identified dual human epidermal growth factor receptor (HER)1/HER2 kinase inhibitors with excellent biochemical potency and kinase selectivity. On the basis of its favorable pharmacokinetic profile and robust in vivo activity in HER1 and HER2 driven tumor models, 13 (BMS-599626) was selected as a clinical candidate for treatment of solid tumors.
Assuntos
Antineoplásicos/síntese química , Carbamatos/síntese química , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Triazinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Linhagem Celular Tumoral , Cães , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Macaca fascicularis , Camundongos , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologiaRESUMO
Pyrrolotriazine dual EGFR/HER2 kinase inhibitors with a 5-((4-aminopiperidin-1-yl)methyl) solubilizing group were found to be superior to analogs with previously reported C-5 solubilizing groups. New synthetic methodology was developed for the parallel synthesis of C-4 analogs with the new solubilizing group. Interesting new leads were evaluated in tumor xenograft models and the C-4 aminofluorobenzylindazole, 1c, was found to exhibit the best antitumor activity. It is hypothesized that this solubilizing group extends into the ribose-phosphate portion of the ATP binding pocket and enhances the binding affinity of the inhibitor.
Assuntos
Química Farmacêutica/métodos , Receptores ErbB/química , Neoplasias/tratamento farmacológico , Piperidinas/síntese química , Pirróis/síntese química , Receptor ErbB-2/química , Triazinas/síntese química , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Insetos , Modelos Químicos , Transplante de Neoplasias , Piperidinas/química , Piperidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Triazinas/química , Triazinas/farmacologiaRESUMO
2-aminothiazole (1) was discovered as a novel Src family kinase inhibitor template through screening of our internal compound collection. Optimization through successive structure-activity relationship iterations identified analogs 2 (Dasatinib, BMS-354825) and 12m as pan-Src inhibitors with nanomolar to subnanomolar potencies in biochemical and cellular assays. Molecular modeling was used to construct a putative binding model for Lck inhibition by this class of compounds. The framework of key hydrogen-bond interactions proposed by this model was in agreement with the subsequent, published crystal structure of 2 bound to structurally similar Abl kinase. The oral efficacy of this class of inhibitors was demonstrated with 12m in inhibiting the proinflammatory cytokine IL-2 ex vivo in mice (ED50 approximately 5 mg/kg) and in reducing TNF levels in an acute murine model of inflammation (90% inhibition in LPS-induced TNFalpha production when dosed orally at 60 mg/kg, 2 h prior to LPS administration). The oral efficacy of 12m was further demonstrated in a chronic model of adjuvant arthritis in rats with established disease when administered orally at 0.3 and 3 mg/kg twice daily. Dasatinib (2) is currently in clinical trials for the treatment of chronic myelogenous leukemia.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Pirimidinas/síntese química , Tiazóis/síntese química , Quinases da Família src/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Artrite Experimental/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Dasatinibe , Feminino , Humanos , Técnicas In Vitro , Inflamação/sangue , Inflamação/induzido quimicamente , Interleucina-2/antagonistas & inibidores , Lipopolissacarídeos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Modelos Moleculares , Ligação Proteica , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tiazóis/química , Tiazóis/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A novel series of 17beta-hydroxysteroid dehydrogenase type 3 (17beta-HSD3) inhibitors has been identified. These inhibitors, based on a dibenzazocine core, exhibited picomolar to low nanomolar inhibition of 17beta-HSD3 in cell-free enzymatic as well as in cell-based transcriptional reporter assays.
Assuntos
17-Hidroxiesteroide Desidrogenases/antagonistas & inibidores , Azocinas , Inibidores Enzimáticos , 17-Hidroxiesteroide Desidrogenases/metabolismo , Fosfatase Alcalina/efeitos dos fármacos , Fosfatase Alcalina/metabolismo , Androstenodiona/metabolismo , Azocinas/síntese química , Azocinas/química , Azocinas/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Testosterona/biossínteseRESUMO
A series of substituted 2-(aminopyridyl)- and 2-(aminopyrimidinyl)thiazole-5-carboxamides was identified as potent Src/Abl kinase inhibitors with excellent antiproliferative activity against hematological and solid tumor cell lines. Compound 13 was orally active in a K562 xenograft model of chronic myelogenous leukemia (CML), demonstrating complete tumor regressions and low toxicity at multiple dose levels. On the basis of its robust in vivo activity and favorable pharmacokinetic profile, 13 was selected for additional characterization for oncology indications.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Pirimidinas/farmacologia , Tiazóis/farmacologia , Quinases da Família src/antagonistas & inibidores , Trifosfato de Adenosina/metabolismo , Animais , Dasatinibe , Humanos , Células K562 , Camundongos , Proteínas Proto-Oncogênicas c-abl/química , Pirimidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Tiazóis/farmacocinética , Quinases da Família src/químicaRESUMO
A series of substituted 2-(aminoheteroaryl)-thiazole-5-carboxamide analogs have been synthesized as novel, potent inhibitors of the Src-family kinase p56Lck. Among them, compound 2 displayed superior in vitro potency and excellent in vivo efficacy.
Assuntos
Amidas/farmacologia , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Tiazóis/farmacologia , Quinases da Família src/antagonistas & inibidores , Administração Oral , Amidas/síntese química , Amidas/farmacocinética , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/terapia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Masculino , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.
Assuntos
Anti-Inflamatórios/química , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Quinoxalinas/química , Quinoxalinas/farmacocinética , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Citocinas/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Ligação de Hidrogênio , Concentração Inibidora 50 , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirazinas/química , Pirazinas/farmacologia , Quinoxalinas/farmacologia , Quinases da Família src/antagonistas & inibidoresRESUMO
Resistance to the ABL kinase inhibitor imatinib (STI571 or Gleevec) in chronic myeloid leukemia (CML) occurs through selection for tumor cells harboring BCR-ABL kinase domain point mutations that interfere with drug binding. Crystallographic studies predict that most imatinib-resistant mutants should remain sensitive to inhibitors that bind ABL with less stringent conformational requirements. BMS-354825 is an orally bioavailable ABL kinase inhibitor with two-log increased potency relative to imatinib that retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants. BMS-354825 prolongs survival of mice with BCR-ABL-driven disease and inhibits proliferation of BCR-ABL-positive bone marrow progenitor cells from patients with imatinib-sensitive and imatinib-resistant CML. These data illustrate how molecular insight into kinase inhibitor resistance can guide the design of second-generation targeted therapies.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Substituição de Aminoácidos , Animais , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Benzamidas , Sítios de Ligação , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Ensaios Clínicos Fase I como Assunto , Dasatinibe , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Humanos , Mesilato de Imatinib , Camundongos , Camundongos SCID , Mutação , Piperazinas/uso terapêutico , Conformação Proteica , Pirimidinas/metabolismo , Pirimidinas/uso terapêutico , Tiazóis/metabolismo , Tiazóis/uso terapêutico , TransfecçãoRESUMO
A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
Assuntos
Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Indóis/farmacologia , Catálise , Cinética , Relação Estrutura-AtividadeRESUMO
A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Canabinoides/metabolismo , Indóis/síntese química , Norbornanos/síntese química , Piridonas/síntese química , Receptores de Droga/agonistas , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Cricetinae , Desenho de Fármacos , Feminino , Humanos , Indóis/química , Indóis/farmacologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucócitos Mononucleares/metabolismo , Ligantes , Lipopolissacarídeos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Conformação Molecular , Norbornanos/química , Norbornanos/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptores de Canabinoides , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Oxazóis/síntese química , Oxazóis/farmacologia , Avaliação Pré-Clínica de Medicamentos , Escherichia coli/enzimologia , Humanos , NAD/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Fenômenos Químicos , Físico-Química , Cristalografia por Raios X , Humanos , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/enzimologiaRESUMO
The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Quinolonas/síntese química , Quinolonas/farmacologia , Humanos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of anilino(imidazoquinoxaline) analogues bearing solubilizing side chains at the 6- and 7-positions of the fused phenyl ring has been prepared and evaluated for inhibition against Lck enzyme and of T-cell proliferation. Significant improvement of the cellular activity was achieved over the initial lead, compound 2.