RESUMO
The development of molecularly targeted agents has benefited from use of pharmacodynamic markers to identify "biologically effective doses" (BED) below MTDs, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such pharmacodynamics-based BED regimens and effectiveness comparisons using MET kinase small-molecule inhibitors. Utilizing pharmacodynamic biomarker measurements of MET signaling (tumor pY1234/1235MET/total MET ratio) in a phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pY1234/1235MET/total MET of 95%-99% were achievable with tolerable doses of EMD1214063/MSC2156119J (tepotinib), XL184 (cabozantinib), and XL880/GSK1363089 (foretinib), but not ARQ197 (tivantinib), which did not alter the pharmacodynamic biomarker. Duration of kinase suppression and rate of kinase recovery were specific to each agent, emphasizing the importance of developing customized dosage regimens to achieve continuous suppression of the pharmacodynamic biomarker at the required level (here, ≥90% MET kinase suppression). The customized dosage regimen of each inhibitor yielded substantial and sustained tumor regression; the equivalent effectiveness of customized dosage regimens that achieve the same level of continuous molecular target control represents preclinical proof-of-concept and illustrates the importance of proper scheduling of targeted agent BEDs. Pharmacodynamics-guided biologically effective dosage regimens (PD-BEDR) potentially offer a superior alternative to pharmacokinetic guidance (e.g., drug concentrations in surrogate tissues) for developing and making head-to-head comparisons of targeted agents. Mol Cancer Ther; 17(3); 698-709. ©2018 AACR.
Assuntos
Desenvolvimento de Medicamentos/métodos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Anilidas/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos Nus , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-met/metabolismo , Piridazinas/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Quinolinas/farmacologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacosRESUMO
Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose-response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489-98. ©2017 AACR.
Assuntos
Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Oncologia/tendências , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
The synthesis and structure-activity relationship (SAR) of a novel series of di-substituted imidazoles, derived from modification of DAPT, are described. Subsequent optimization led to identification of a highly potent series of inhibitors that contain a ß-amine in the imidazole side-chain resulting in a robust in vivo reduction of plasma and brain Aß in guinea pigs. The therapeutic index between Aß reductions and changes in B-cell populations were studied for compound 10 h.
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Aminação/efeitos dos fármacos , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/metabolismo , Animais , Bioensaio , Diamida/síntese química , Diamida/química , Diamida/farmacologia , Inibidores Enzimáticos/química , Cobaias , Células HeLa , Humanos , Imidazóis/química , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aß in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aß EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Valina/análogos & derivados , Animais , Bioensaio , Desenho de Fármacos , Inibidores Enzimáticos/química , Cobaias , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Valina/síntese química , Valina/química , Valina/farmacologiaRESUMO
PF-3084014 [(S)-2-((S)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-N-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1H-imidazol-4-yl)pentanamide] is a novel gamma-secretase inhibitor that reduces amyloid-beta (Abeta) production with an in vitro IC(50) of 1.2 nM (whole-cell assay) to 6.2 nM (cell-free assay). This compound inhibits Notch-related T- and B-cell maturation in an in vitro thymocyte assay with an EC(50) of 2.1 microM. A single acute dose showed dose-dependent reduction in brain, cerebrospinal fluid (CSF), and plasma Abeta in Tg2576 mice as measured by enzyme-linked immunosorbent assay and immunoprecipitation (IP)/mass spectrometry (MS). Guinea pigs were dosed with PF-3084014 for 5 days via osmotic minipump at 0.03 to 3 mg/kg/day and exhibited dose-dependent reduction in brain, CSF, and plasma Abeta. To further characterize Abeta dynamics in brain, CSF, and plasma in relation to drug exposure and Notch-related toxicities, guinea pigs were dosed with 0.03 to 10 mg/kg PF-3084014, and tissues were collected at regular intervals from 0.75 to 30 h after dose. Brain, CSF, and plasma all exhibited dose-dependent reductions in Abeta, and the magnitude and duration of Abeta lowering exceeded those of the reductions in B-cell endpoints. Other gamma-secretase inhibitors have shown high potency at elevating Abeta in the conditioned media of whole cells and the plasma of multiple animal models and humans. Such potentiation was not observed with PF-3084014. IP/MS analysis, however, revealed dose-dependent increases in Abeta11-40 and Abeta1-43 at doses that potently inhibited Abeta1-40 and Abeta1-42. PF-3084014, like previously described gamma-secretase inhibitors, preferentially reduced Abeta1-40 relative to Abeta1-42. Potency at Abeta relative to Notch-related endpoints in vitro and in vivo suggests that a therapeutic index can be achieved with this compound.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Tetra-Hidronaftalenos/farmacologia , Tetra-Hidronaftalenos/farmacocinética , Valina/análogos & derivados , Animais , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Linhagem Celular , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Escherichia coli/genética , Feminino , Cobaias , Humanos , Contagem de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Baço/citologia , Baço/efeitos dos fármacos , Tetra-Hidronaftalenos/efeitos adversos , Tetra-Hidronaftalenos/química , Distribuição Tecidual , Transfecção , Valina/efeitos adversos , Valina/química , Valina/farmacocinética , Valina/farmacologiaRESUMO
The thiazole-diamide series (1) has been identified as highly potent gamma-secretase inhibitors. Several representative compounds showed IC(50) values of <0.3 nM. The synthesis and SAR, as well as a radiolabeled synthesis of [(3)H]-2a, are described.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Diamida/química , Diamida/farmacologia , Tiazóis/química , Alquilação , Aminação , Secretases da Proteína Precursora do Amiloide/metabolismo , Sistema Livre de Células , Diamida/síntese química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-AtividadeAssuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/biossíntese , Fragmentos de Peptídeos/biossíntese , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Animais , Celecoxib , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Humanos , Camundongos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Pirazóis/sangue , Pirazóis/uso terapêutico , Sulfonamidas/sangue , Sulfonamidas/uso terapêuticoRESUMO
The synthesis and nNOS and eNOS activity of 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-5-ethyl-2-methoxyphenyl)-pyridin-2-ylamines and 6-(4-(dimethylaminoalkyl)-/6-(4-(dimethylaminoalkoxy)-2,5-dimethoxyphenyl)-pyridin-2-ylamines 1-8 are described. These compounds are potent inhibitors of the human nNOS isoform.
Assuntos
Aminas/química , Inibidores Enzimáticos/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Óxido Nítrico Sintase/antagonistas & inibidores , Piridinas/química , Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Inibição Neural/efeitos dos fármacos , Óxido Nítrico Sintase Tipo I , Piridinas/farmacologiaRESUMO
The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.
Assuntos
Aminopiridinas/síntese química , Óxido Nítrico Sintase/antagonistas & inibidores , Tetra-Hidronaftalenos/síntese química , Aminopiridinas/química , Aminopiridinas/farmacologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , GMP Cíclico/biossíntese , Masculino , Atividade Motora/efeitos dos fármacos , Óxido Nítrico Sintase/química , Óxido Nítrico Sintase Tipo I , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/química , Tetra-Hidronaftalenos/farmacologiaRESUMO
Cholinesterase inhibitors vary in their selectivity for acetylcholinesterase versus butyrylcholinesterase. We examined several cholinesterase inhibitors and assessed the relative role of acetylcholinesterase versus butyrylcholinesterase inhibition in central and peripheral responses to these medications. Donepezil and icopezil are highly selective for acetylcholinesterase, whereas tacrine and heptylphysostigmine demonstrated greater potency for butyrylcholinesterase over acetylcholinesterase. All four compounds increased acetylcholine levels in mouse brains. Dose-response curves for tremor (central effect) and salivation (peripheral effect) showed that donepezil and icopezil possess a more favourable therapeutic index than the nonselective inhibitors, tacrine and heptylphysostigmine. Co-administration of the selective butyrylcholinesterase inhibitor tetraisopropylpyrophosphoramide (iso-OMPA) potentiated peripheral, but not central, effects of the selective acetylcholinesterase inhibitor icopezil. The improved therapeutic index observed in mice with icopezil is due to a high degree of selectivity for acetylcholinesterase versus butyrylcholinesterase, suggesting that high selectivity for acetylcholinesterase may contribute to the clinically favourable tolerability profile of agents such as donepezil in Alzheimer's disease patients.