RESUMO
A series of 2-(1H-pyrazol-1-yl)pyridines are described as inhibitors of ALK5 (TGFß receptor I kinase). Modeling compounds in the ALK5 kinase domain enabled some optimization of potency via substitutions on the pyrazole core. One of these compounds PF-03671148 gave a dose dependent reduction in TGFß induced fibrotic gene expression in human fibroblasts. A similar reduction in fibrotic gene expression was observed when PF-03671148 was applied topically in a rat wound repair model. Thus these compounds have potential utility for the prevention of dermal scarring.
Assuntos
Cicatriz/prevenção & controle , Descoberta de Drogas , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/química , Piridinas/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Pele/efeitos dos fármacos , Animais , Modelos Moleculares , Fosforilação , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo IRESUMO
A series of pantolactam based compounds were identified as potent antagonists for the androgen receptor (AR). Those that possessed properties suitable for topical delivery were evaluated in the validated Hamster Ear Model. Several compounds were found to be efficacious in reducing wax esters, a major component of sebum, initiating further preclinical work on these compounds.
Assuntos
Antagonistas de Receptores de Andrógenos/farmacologia , Ésteres/metabolismo , Lactamas/farmacologia , Sebo/efeitos dos fármacos , Ceras/metabolismo , Administração Tópica , Antagonistas de Receptores de Andrógenos/síntese química , Antagonistas de Receptores de Andrógenos/química , Animais , Cricetinae , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ésteres/química , Lactamas/síntese química , Lactamas/química , Modelos Animais , Modelos Moleculares , Estrutura Molecular , Receptores Androgênicos/metabolismo , Sebo/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Ceras/químicaRESUMO
A series of diphenyl ethers was prepared and evaluated for androgen receptor antagonist activity in human androgen receptor binding and cellular functional assays. Analogs with potent in vitro activities were evaluated for topical in vivo efficacy in the Golden Syrian Hamster ear model. Several compounds showed reduction in wax esters in this validated animal model.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Antagonistas de Androgênios/química , Antagonistas de Receptores de Andrógenos , Éteres Fenílicos/administração & dosagem , Éteres Fenílicos/síntese química , Sebo/efeitos dos fármacos , Sebo/metabolismo , Administração Tópica , Animais , Linhagem Celular Tumoral , Cricetinae , Humanos , Masculino , Mesocricetus , Receptores Androgênicos/química , Reprodutibilidade dos TestesRESUMO
Signaling through the erbB receptor family of tyrosine kinases contributes to the proliferation, differentiation, migration, and survival of a variety of cell types. Abnormalities in members of this receptor family have been shown to play a role in oncogenesis, thus making them attractive targets for anticancer treatments. PF-00299804 is a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor currently in phase I clinical trials. PF-00299804 is believed to irreversibly inhibit erbB tyrosine kinase activity through binding at the ATP site and covalent modification of nucleophilic cysteine residues in the catalytic domains of erbB family members. Oral administration of PF-00299804 causes significant antitumor activity, including marked tumor regressions in a variety of human tumor xenograft models that express and/or overexpress erbB family members or contain the double mutation (L858R/T790M) in erbB1 (EGFR) associated with resistance to gefitinib and erlotinib. Furthermore, PF-00299804 shows exceptional distribution to human tumor xenografts and excellent pharmacokinetic properties across species.
Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Quinazolinonas/farmacologia , Quinazolinonas/farmacocinética , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto , Substituição de Aminoácidos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Feminino , Humanos , Camundongos , Camundongos SCID , Mutação/genética , Fosforilação/efeitos dos fármacos , Especificidade da EspécieRESUMO
A new series of alpha-aryl or alpha-heteroarylphenyl propanoic acid derivatives was synthesized that incorporate acetylene-, ethylene-, propyl-, or nitrogen-derived linkers as a replacement of the commonly used ether moiety that joins the central phenyl ring with the lipophilic tail. The effect of these modifications in the binding and activation of PPARalpha and PPARgamma was first evaluated in vitro. Compounds possessing suitable profiles were then evaluated in the ob/ob mouse model of type 2 diabetes. The propylene derivative 40 and the propyl derivative 53 demonstrated robust plasma glucose lowering activity in this model. Compound 53 was also evaluated in male Zucker diabetic fatty rats and was found to achieve normalization of glucose, triglycerides, and insulin levels. An X-ray crystal structure of the complex of 53 with the PPARgamma-ligand-binding domain was obtained and discussed in this report.
Assuntos
PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos , Administração Oral , Animais , Cristalografia por Raios X , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Obesos , Modelos Moleculares , Estrutura Molecular , Fenilpropionatos/síntese química , Fenilpropionatos/química , Fenilpropionatos/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structure-activity relationships for inhibition of erbB1, erbB2, and erbB4 were determined for a series of quinazoline- and pyrido[3,4-d]pyrimidine-based analogues of the irreversible pan-erbB inhibitor, canertinib. Cyclic amine bearing crotonamides were determined to provide rapid inhibition of cellular erbB1 autophosphorylation and good metabolic stability in liver microsome and hepatocyte assays. The influence of 4-anilino substitution on pan-erbB inhibitory potency was investigated. Several anilines were identified as providing potent, reversible pan-erbB inhibition. Optimum 4- and 6-substituents with known 7-substituents provided preferred irreversible inhibitors for pharmacodynamic testing in vivo. Quinazoline 54 and pyrido[3,4-d]pyrimidine 71 were identified as clearly superior to canertinib. Both compounds possess a piperidinyl crotonamide Michael acceptor and a 3-chloro-4-fluoroaniline, indicating these as optimized 6- and 4-substituents, respectively. Pharmacokinetic comparison of compounds 54 and 71 across three species selected compound 54 as the preferred candidate. Compound 54 (PF-00299804) has been assigned the nomenclature of dacomitinib and is currently under clinical evaluation.
Assuntos
Antineoplásicos/química , Receptores ErbB/antagonistas & inibidores , Morfolinas/química , Piridinas/química , Pirimidinas/química , Quinazolinas/química , Quinazolinonas/química , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Cães , Xenoenxertos , Humanos , Injeções Intravenosas , Macaca fascicularis , Masculino , Camundongos Nus , Morfolinas/síntese química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Transplante de Neoplasias , Fosforilação , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Quinazolinonas/síntese química , Quinazolinonas/farmacocinética , Quinazolinonas/farmacologia , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Developing molecularly targeted therapeutics with minimal off-target effects is facilitated by an understanding of compound selectivity. However, for HDAC inhibitors, a clear understanding of specificity has been challenging. In particular, it has been suggested that use of nonspecific substrates and the presence of multiple HDAC activities in enzyme preparations may complicate interpretation of inhibitor experiments. To overcome these and other potential limitations of activity-based HDAC assays, the authors have developed an assay format based on measurement of the binding affinity of inhibitors rather than measurement of enzyme activity. One advantage of this format is that it does not require use of a substrate and thus ameliorates concerns about lack of specificity of existing substrates. This assay is based on an Alexa Fluor® 647-labeled HDAC inhibitor or "tracer," which binds with a high affinity to Class I and Class IIb HDACs. Unlike activity assays, which can be affected by the presence of residual untagged endogenous HDACs from the host expression system, the signal in this format is dependent on the presence of an epitope tag on the specific HDAC of interest. The authors demonstrate the utility of this method by determining the potencies of commonly used inhibitors for six human HDACs.
Assuntos
Ensaios Enzimáticos/métodos , Transferência Ressonante de Energia de Fluorescência/métodos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Cinética , Ligação Proteica/efeitos dos fármacosRESUMO
Farnesyltransferase inhibitors (FTIs) have been developed as potential anti-cancer agents due to their efficacy in blocking malignant growth in a variety of murine models of human tumors. To that end, we have developed a series of pyridone farnesyltransferase inhibitors with potent in vitro and cellular activity. The synthesis, SAR and biological properties of these compounds will be discussed.