RESUMO
A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 µM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 µM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinase 1 Polo-LikeRESUMO
ABT-348 [1-(4-(4-amino-7-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)thieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea] is a novel ATP-competitive multitargeted kinase inhibitor with nanomolar potency (IC(50)) for inhibiting binding and cellular autophosphorylation of Aurora B (7 and 13 nM), C (1 and 13 nM), and A (120 and 189 nM). Cellular activity against Aurora B is reflected by inhibition of phosphorylation of histone H3, induction of polyploidy, and inhibition of proliferation of a variety of leukemia, lymphoma, and solid tumor cell lines (IC(50) = 0.3-21 nM). In vivo inhibition of Aurora B was confirmed in an engrafted leukemia model by observing a decrease in phosphorylation of histone H3 that persisted in a dose-dependent manner for 8 h and correlated with plasma concentration of ABT-348. Evaluation of ABT-348 across a panel of 128 kinases revealed additional potent binding activity (K(i) < 30 nM) against vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) families and the Src family of cytoplasmic tyrosine kinases. VEGFR/PDGFR binding activity correlated with inhibition of autophosphorylation in cells and inhibition of vascular endothelial growth factor (VEGF)-stimulated endothelial cell proliferation (IC(50) ≤ 0.3 nM). Evidence of on-target activity in vivo was provided by the potency for blocking VEGF-mediated vascular permeability and inducing plasma placental growth factor. Activity against the Src kinase family was evident in antiproliferative activity against BCR-ABL chronic myeloid leukemia cells and cells expressing the gleevec-resistant BCR-ABL T315I mutation. On the basis of its unique spectrum of activity, ABT-348 was evaluated and found effective in representative solid tumor [HT1080 and pancreatic carcinoma (MiaPaCa), tumor stasis] and hematological malignancy (RS4;11, regression) xenografts. These results provide the rationale for clinical assessment of ABT-348 as a therapeutic agent in the treatment of cancer.
Assuntos
Aminopiridinas/farmacologia , Antineoplásicos/farmacologia , Compostos de Fenilureia/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Quinases da Família src/antagonistas & inibidores , Aminopiridinas/química , Aminopiridinas/farmacocinética , Aminopiridinas/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Histonas/antagonistas & inibidores , Células Endoteliais da Veia Umbilical Humana , Humanos , Leucemia Experimental/tratamento farmacológico , Leucemia Experimental/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Estrutura Molecular , Células NIH 3T3 , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Compostos de Fenilureia/uso terapêutico , Fatores de Tempo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PARP-1, the most abundant member of the PARP superfamily of nuclear enzymes, has emerged as a promising molecular target in the past decade particularly for the treatment of cancer. A number of PARP-1 inhibitors, including veliparab discovered at Abbott, have advanced into different stages of clinical trials. Herein we describe the development of a new tetrahydropyridopyridazinone series of PARP-1 inhibitors. Many compounds in this class, such as 20w, displayed excellent potency against the PARP-1 enzyme with a K(i) value of <1nM and an EC(50) value of 1nM in a C41 whole cell assay. The presence of the NH in the tetrahydropyridyl ring of the tetrahydropyridopyridazinone scaffold improved the pharmacokinetic properties over similar carbon based analogs. Compounds 8c and 20u are orally available, and have demonstrated significant efficacy in a B16 murine xenograft model, potentiating the efficacy of temozolomide (TMZ).
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Piridazinas/farmacologia , Piridinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/enzimologia , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/metabolismo , Piridazinas/síntese química , Piridazinas/química , Piridinas/síntese química , Piridinas/química , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
In an effort to identify kinase inhibitors with dual KDR/Aurora B activity and improved aqueous solubility compared to the Abbott dual inhibitor ABT-348, a series of novel pyrazole pyrimidines structurally related to kinase inhibitor AS703569 were prepared. SAR work provided analogs with significant cellular activity, measureable aqueous solubility and moderate antitumor activity in a mouse tumor model after weekly ip dosing. Unfortunately these compounds were pan-kinase inhibitors that suffered from narrow therapeutic indices which prohibited their use as antitumor agents.
Assuntos
Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Aminação , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Aurora Quinase B , Aurora Quinases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Moleculares , Estrutura Molecular , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Four hinge-binding scaffolds have been explored for novel selective Aurora kinase inhibitors. The structure activity relationship, selectivity and pharmacokinetic profiles have been evaluated.
Assuntos
Inibidores de Proteínas Quinases/síntese química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Animais , Aurora Quinases , Linhagem Celular , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-AtividadeRESUMO
In an effort to identify multi-targeted kinase inhibitors with a novel spectrum of kinase activity, a screen of Abbott proprietary KDR inhibitors against a broad panel of kinases was conducted and revealed a series of thienopyridine ureas with promising activity against the Aurora kinases. Modification of the diphenyl urea and C7 moiety of these compounds provided potent inhibitors with good pharmacokinetic profiles that were efficacious in mouse tumor models after oral dosing. Compound 2 (ABT-348) of this series is currently undergoing Phase I clinical trials in solid and hematological cancer populations.
Assuntos
Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Ureia/farmacologia , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Humanos , Camundongos , Inibidores de Proteínas Quinases/química , Fator A de Crescimento do Endotélio VascularRESUMO
In an effort to discover Aurora kinase inhibitors, an HTS hit revealed an amide containing pyrrolopyrimidine compound. Replacement of the pyrrolopyrimidine residue with a thienopyrimidine moiety led to a series of potent and selective Aurora inhibitors.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Animais , Aurora Quinases , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Ligação de Hidrogênio , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A new quantitation method for mass spectrometry imaging (MSI) with matrix-assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 µm tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The integrated MSI response was correlated to the LC/MS/MS drug concentrations to determine the amount of drug detected per MSI ion count. The study reported here evaluates olanzapine in liver tissue. Tissue samples containing a range of concentrations were created from liver harvested from rats administered a single dose of olanzapine at 0, 1, 4, 8, 16, 30, or 100 mg/kg. The liver samples were then analyzed by MALDI-MSI and LC/MS/MS. The MALDI-MSI and LC/MS/MS correlation was determined for tissue concentrations of ~300 to 60,000 ng/g and yielded a linear relationship over two orders of magnitude (R(2) = 0.9792). From this correlation, a conversion factor of 6.3 ± 0.23 fg/ion count was used to quantitate MSI responses at the pixel level (100 µm). The details of the method, its importance in pharmaceutical analysis, and the considerations necessary when implementing it are presented.
Assuntos
Histocitoquímica/métodos , Imagem Molecular/métodos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Animais , Benzodiazepinas/administração & dosagem , Benzodiazepinas/farmacocinética , Cromatografia Líquida , Modelos Lineares , Fígado/química , Fígado/metabolismo , Masculino , Olanzapina , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Distribuição TecidualRESUMO
This Letter describes the lead discovery, optimization, and biological characterization of a series of substituted 4-amino-1H-pyrazolo[3,4-d]pyrimidines as potent inhibitors of IGF1R, EGFR, and ErbB2. The leading compound 11 showed an IGF1R IC(50) of 12 nM, an EGFR (L858R) IC(50) of 31 nM, and an ErbB2 IC(50) of 11 nM, potent activity in cellular functional and anti-proliferation assays, as well as activity in an in vivo pharmacodynamic assay.
Assuntos
Adenina/análogos & derivados , Antineoplásicos/química , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Receptor ErbB-2/antagonistas & inibidores , Receptor IGF Tipo 1/antagonistas & inibidores , Adenina/química , Adenina/farmacocinética , Adenina/farmacologia , Animais , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/tratamento farmacológico , Ratos , Receptor ErbB-2/metabolismo , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-AtividadeRESUMO
We have developed a series of phenylpyrrolidine- and phenylpiperidine-substituted benzimidazole carboxamide poly(ADP-ribose) polymerase (PARP) inhibitors with excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of (S)-2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)-1H-benzimidazole-4-carboxamide (22b, A-966492). Compound 22b displayed excellent potency against the PARP-1 enzyme with a K(i) of 1 nM and an EC(50) of 1 nM in a whole cell assay. In addition, 22b is orally bioavailable across multiple species, crosses the blood-brain barrier, and appears to distribute into tumor tissue. It also demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide and in an MX-1 breast cancer xenograft model both as a single agent and in combination with carboplatin.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteína BRCA1/deficiência , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Cristalografia por Raios X , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Modelos Moleculares , Transplante de Neoplasias , Estereoisomerismo , Relação Estrutura-Atividade , Temozolomida , Transplante HeterólogoRESUMO
Small molecule inhibitors of PARP-1 have been pursued by various organizations as potential therapeutic agents either capable of sensitizing cytotoxic treatments or acting as stand-alone agents to combat cancer. As one of the strategies to expand our portfolio of PARP-1 inhibitors, we pursued unsaturated heterocycles to replace the saturated cyclic amine derivatives appended to the benzimidazole core. Not only did a variety of these new generation compounds maintain high enzymatic potency, many of them also displayed robust cellular activity. For example, the enzymatic IC(50) and cellular EC(50) values were as low as 1 nM or below. Compounds 24 (EC(50) = 3.7 nM) and 44 (EC(50) = 7.8 nM), featuring an oxadiazole and a pyridine moiety, respectively, demonstrated balanced potency and PK profiles. In addition, these two molecules exhibited potent oral in vivo efficacy in potentiating the cytotoxic agent temozolomide in a B16F10 murine melanoma model.
Assuntos
Antineoplásicos/síntese química , Benzimidazóis/síntese química , Oxidiazóis/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Piridinas/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Masculino , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Poli(ADP-Ribose) Polimerase-1 , Piridinas/farmacocinética , Piridinas/farmacologia , Relação Estrutura-Atividade , Temozolomida , Transplante HeterólogoRESUMO
Pim-1, Pim-2, and Pim-3 are a family of serine/threonine kinases which have been found to be overexpressed in a variety of hematopoietic malignancies and solid tumors. Benzothienopyrimidinones were discovered as a novel class of Pim inhibitors that potently inhibit all three Pim kinases with subnanomolar to low single-digit nanomolar K(i) values and exhibit excellent selectivity against a panel of diverse kinases. Protein crystal structures of the bound Pim-1 complexes of benzothienopyrimidinones 3b (PDB code 3JYA), 6e (PDB code 3JYO), and 12b (PDB code 3JXW) were determined and used to guide SAR studies. Multiple compounds exhibited potent antiproliferative activity in K562 and MV4-11 cells with submicromolar EC(50) values. For example, compound 14j inhibited the growth of K562 cells with an EC(50) value of 1.7 muM and showed K(i) values of 2, 3, and 0.5 nM against Pim-1, Pim-2, and Pim-3, respectively. These novel Pim kinase inhibitors efficiently interrupted the phosphorylation of Bad in both K562 and LnCaP-Bad cell lines, indicating that their potent biological activities are mechanism-based. The pharmacokinetics of 14j was studied in CD-1 mice and shown to exhibit bioavailability of 76% after oral dosing. ADME profiling of 14j suggested a long half-life in both human and mouse liver microsomes, good permeability, modest protein binding, and no CYP inhibition below 20 muM concentration.
Assuntos
Antineoplásicos/síntese química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinonas/síntese química , Tiofenos/síntese química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Fosforilação , Conformação Proteica , Proteínas Proto-Oncogênicas c-pim-1/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia , Proteína de Morte Celular Associada a bcl/metabolismoRESUMO
Based on screening hit 1, a series of tricyclic quinoxalinones have been designed and evaluated for inhibition of PARP-1. Substitutions at the 7- and 8-positions of the quinoxalinone ring led to a number of compounds with good enzymatic and cellular potency. The tricyclic quinoxalinone class is sensitive to modifications of both the amine substituent and the tricyclic core. The synthesis and structure-activity relationship studies are presented.
Assuntos
Química Farmacêutica/métodos , Inibidores de Poli(ADP-Ribose) Polimerases , Quinoxalinas/química , Quinoxalinas/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Apoptose , Núcleo Celular/metabolismo , Reparo do DNA , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinética , Modelos Moleculares , Conformação Molecular , Niacinamida/química , Relação Estrutura-AtividadeRESUMO
Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/métodos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Dimerização , Desenho de Fármacos , Humanos , Pulmão/metabolismo , Modelos Químicos , Neoplasias/metabolismo , Fosforilação , Pirimidinas/química , Receptores Proteína Tirosina Quinases/química , Transdução de SinaisRESUMO
We have developed a series of cyclic amine-containing benzimidazole carboxamide PARP inhibitors with a methyl-substituted quaternary center at the point of attachment to the benzimidazole ring system. These compounds exhibit excellent PARP enzyme potency as well as single-digit nanomolar cellular potency. These efforts led to the identification of 3a (2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide, ABT-888), currently in human phase I clinical trials. Compound 3a displayed excellent potency against both the PARP-1 and PARP-2 enzymes with a K(i) of 5 nM and in a C41 whole cell assay with an EC(50) of 2 nM. In addition, 3a is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast cancer xenograft model in combination with either carboplatin or cyclophosphamide.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Inibidores Enzimáticos/farmacologia , Melanoma Experimental/patologia , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Área Sob a Curva , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Carboplatina/administração & dosagem , Ciclofosfamida/administração & dosagem , Dacarbazina/administração & dosagem , Dacarbazina/análogos & derivados , Cães , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Feminino , Haplorrinos , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos SCID , Ratos , TemozolomidaRESUMO
ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a pharmacodynamic marker, ADP ribose polymers (pADPr), after ABT 888 treatment. ABT-888 enhanced TMZ antitumor activity, in a dose-proportional manner with no observed toxicity (44-75% tumor growth inhibition vs. TMZ monotherapy), but did not show single agent activity. Extended ABT-888 dosing schedules showed no advantage compared to simultaneous TMZ administration. Efficacy correlated with plasma/tumor drug concentrations. Intratumor drug levels correlated with a dose-proportional/time-dependent reduction in pADPr. Potentiation of TMZ activity by ABT-888 correlated with drug levels and inhibition of PARP activity in vivo. ABT-888 is in Phase 1 trials using a validated ELISA based on the assay developed here to assess pharmacological effect.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Dacarbazina/análogos & derivados , Melanoma Experimental/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Dacarbazina/administração & dosagem , Dacarbazina/farmacocinética , Dacarbazina/farmacologia , Esquema de Medicação , Sinergismo Farmacológico , Melanoma Experimental/enzimologia , Melanoma Experimental/metabolismo , Camundongos , Poli Adenosina Difosfato Ribose/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , TemozolomidaRESUMO
Poly(ADP-ribose) polymerases (PARPs) play significant roles in various cellular functions including DNA repair and control of RNA transcription. PARP inhibitors have been demonstrated to potentiate the effect of cytotoxic agents or radiation in a number of animal tumor models. Utilizing a benzimidazole carboxamide scaffold in which the amide forms a key intramolecular hydrogen bond for optimal interaction with the enzyme, we have identified a novel series of PARP inhibitors containing a quaternary methylene-amino substituent at the C-2 position of the benzimidazole. Geminal dimethyl analogs at the methylene-amino substituent were typically more potent than mono-methyl derivatives in both intrinsic and cellular assays. Smaller cycloalkanes such as cyclopropyl or cyclobutyl were tolerated at the quaternary carbon while larger rings were detrimental to potency. In vivo efficacy data in a B16F10 murine flank melanoma model in combination with temozolomide (TMZ) are described for two optimized analogs.
Assuntos
Antineoplásicos/síntese química , Química Farmacêutica/instrumentação , Inibidores Enzimáticos/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Química Farmacêutica/métodos , DNA/química , Reparo do DNA , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Cinética , Camundongos , Transplante de Neoplasias , Transcrição GênicaRESUMO
We have developed a series of cyclic amine-containing benzimidazole carboxamide poly(ADP-ribose)polymerase (PARP) inhibitors, with good PARP-1 enzyme potency, as well as cellular potency. These efforts led to the identification of a lead preclinical candidate, 10b, 2-(1-propylpiperidin-4-yl)-1H-benzimidazole-4-carboxamide (A-620223). 10b displayed very good potency against both the PARP-1 enzyme with a K(i) of 8nM and in a whole cell assay with an EC(50) of 3nM. 10b is aqueous soluble, orally bioavailable across multiple species, and demonstrated good in vivo efficacy in a B16F10 subcutaneous murine melanoma model in combination with temozolomide (TMZ) and in an MX-1 breast xenograph model in combination with cisplatin.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Neoplasias da Mama/tratamento farmacológico , Melanoma Experimental/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Relação Estrutura-Atividade , Temozolomida , Transplante Heterólogo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
7-Aminopyrazolo[1,5- a]pyrimidine urea receptor tyrosine kinase inhibitors have been discovered. Investigation of structure-activity relationships of the pyrazolo[1,5- a]pyrimidine nucleus led to a series of 6-(4- N, N'-diphenyl)ureas that potently inhibited a panel of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) kinases. Several of these compounds, such as 34a, are potent inhibitors of kinase insert domain-containing receptor tyrosine kinase (KDR) both enzymatically (<10 nM) and cellularly (<10 nM). In addition, compound 34a possesses a favorable pharmacokinetic profile and demonstrates efficacy in the estradiol-induced murine uterine edema (UE) model (ED 50 = 1.4 mg/kg).
Assuntos
Compostos de Fenilureia/síntese química , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Animais , Edema/tratamento farmacológico , Edema/enzimologia , Feminino , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Compostos de Fenilureia/química , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/química , Pirazóis/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/química , Relação Estrutura-Atividade , Ureia/química , Doenças Uterinas/tratamento farmacológico , Doenças Uterinas/enzimologiaRESUMO
A series of benzoisoxazoles and benzoisothiazoles have been synthesized and evaluated as inhibitors of receptor tyrosine kinases (RTKs). Structure-activity relationship studies led to the identification of 3-amino benzo[ d]isoxazoles, incorporating a N, N'-diphenyl urea moiety at the 4-position that potently inhibited both the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor families of RTKs. Within this series, orally bioavailable compounds possessing promising pharmacokinetic profiles were identified, and a number of compounds demonstrated in vivo efficacy in models of VEGF-stimulated vascular permeability and tumor growth. In particular, compound 50 exhibited an ED 50 of 2.0 mg/kg in the VEGF-stimulated uterine edema model and 81% inhibition in the human fibrosarcoma (HT1080) tumor growth model when given orally at a dose of 10 mg/kg/day.