RESUMO
Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.
Assuntos
Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Antineoplásicos/farmacologia , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Receptor ErbB-2/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Receptores ErbB/genética , Receptores ErbB/metabolismoRESUMO
Crizotinib and entrectinib have been approved to treat ROS1 fusion-positive (ROS1+) non-small-cell lung cancer. However, unmet needs remain, including treatment of patients with resistance mutations, efficacy in brain metastasis and avoidance of neurological side effects. Taletrectinib was designed to: improve efficacy; overcome resistance to first-generation ROS1 inhibitors; and address brain metastasis while conferring fewer neurological adverse events. All of these features are demonstrated and supported by the interim data from the regional phase II TRUST-I clinical study. Here we describe the rationale and design of TRUST-II, a global phase II study of taletrectinib in patients with locally advanced/metastatic ROS1+ non-small-cell lung cancer and other ROS1+ solid tumors. The primary end point is confirmed objective response rate. Secondary end points include duration of response, progression-free survival, overall survival and safety. This trial is enrolling patients in North America, Europe and Asia.
The targeted therapies crizotinib and entrectinib are the first options available to treat a type of lung cancer called ROS1 fusion-positive non-small-cell lung cancer (ROS1+ NSCLC). However, not all patients with ROS1+ NSCLC respond to these drugs. In addition, most patients who take these drugs find their cancer eventually develops resistance and begins to grow again. Patients with disease that has spread (metastasized) to the brain have worse outcomes. Taletrectinib is a new type of targeted therapy that is being developed to treat people who have metastatic ROS1+ NSCLC. Data from a regional phase II clinical trial showed that taletrectinib is well tolerated, effective for patients who have never taken a ROS1 targeted therapy and inhibits ROS1+ NSCLC for patients whose cancer has developed some types of resistance to these drugs. It has also been shown to treat ROS1+ NSCLC tumors that have spread to the brain. This article discusses the rationale and design of a new trial called TRUST-II, which is a global phase II clinical trial looking at how well taletrectinib works and how safe it is. TRUST-II is actively enrolling patients in North America, Europe and Asia. Clinical Trial Registration: NCT04919811 (ClinicalTrials.gov).
Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Tirosina Quinases/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Ensaios Clínicos Fase II como AssuntoRESUMO
Treatments for central nervous system diseases with therapeutic antibodies have been increasingly investigated over the last decades, leading to some approved monoclonal antibodies for brain disease therapies. The detection of biomarkers for diagnosis purposes with non-invasive antibody-based imaging approaches has also been explored in brain cancers. However, antibodies generally display a low capability of reaching the brain, as they do not efficiently cross the blood-brain barrier. As an alternative, recent studies have focused on single-domain antibodies (sdAbs) that correspond to the antigen-binding fragment. While some reports indicate that the brain uptake of these small antibodies is still low, the number of studies reporting brain-penetrating sdAbs is increasing. In this review, we provide an overview of methods used to assess or evaluate brain penetration of sdAbs and discuss the pros and cons that could affect the identification of brain-penetrating sdAbs of therapeutic or diagnostic interest.
Assuntos
Anticorpos de Domínio Único , Diagnóstico por Imagem , EncéfaloRESUMO
Ceftaroline, approved to treat skin infections and pneumonia due to methicillin-resistant Staphylococcus aureus (MRSA), has been considered for the treatment of central nervous system (CNS) infections. A population pharmacokinetic (popPK) model was developed to describe ceftaroline soft tissue and cerebrospinal fluid (CSF) distributions and investigate the probability of target attainment (PTA) of the percentage of the dosing interval that the unbound drug concentration exceeded the MIC (%fT>MIC) to treat MRSA infections. Healthy subjects' plasma and microdialysate concentrations from muscle and subcutaneous tissue following 600 mg every 12 h (q12h) and q8h and neurosurgical patients' plasma and CSF concentrations following single 600-mg dosing were used. Plasma concentrations were described by a two-compartment model, and tissue concentrations were incorporated as three independent compartments linked to the central compartment by bidirectional transport (clearance in [CLin] and CLout). Apparent volumes were fixed to physiological interstitial values. Healthy status and body weight were identified as covariates for the volume of the central compartment, and creatinine clearance was identified for clearance. The CSF glucose concentration (GLUC) was inversely correlated with CLin,CSF. Simulations showed a PTA of >90% in plasma and soft tissues for both regimens assuming an MIC of 1 mg/L and a %fT>MIC of 28.8%. Using the same target, patients with inflamed meninges (0.5 < GLUC ≤ 2 mmol/L) would reach PTAs of 99.8% and 97.2% for 600 mg q8h and q12h, respectively. For brain infection with mild inflammation (2 < GLUC ≤ 3.5 mmol/L), the PTAs would be reduced to 34.3% and 9.1%, respectively. Ceftaroline's penetration enhanced by meningeal inflammation suggests that the drug could be a candidate to treat MRSA CNS infections.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Antibacterianos/uso terapêutico , Encéfalo , Cefalosporinas/uso terapêutico , Creatinina , Glucose , Humanos , Inflamação/tratamento farmacológico , Testes de Sensibilidade Microbiana , Probabilidade , CeftarolinaRESUMO
Abemaciclib is the third cyclin-dependent kinase (CDK) 4/6 inhibitor approved for the treatment of breast cancer and currently under investigation for other malignancies, including brain cancer. Primarily CYP3A4 metabolizes abemaciclib, forming three active metabolites (M2, M20 and M18) that are likely relevant for abemaciclib efficacy and toxicity. We investigated the impact of ABCB1 (P-gp), ABCG2 (BCRP) and CYP3A on the pharmacokinetics and tissue distribution of abemaciclib and its metabolites using genetically modified mice. In vitro, abemaciclib was efficiently transported by hABCB1 and mAbcg2, and slightly by hABCG2, but the active metabolites were transported even better. Upon oral administration of 10 mg/kg abemaciclib, absence of Abcg2 and especially Abcb1a/1b significantly increased the plasma AUC0-24 h and Cmax of M2 and M18. Furthermore, the relative brain penetration of abemaciclib, M2 and M20 was dramatically increased by 25-, 4- and 60-fold, respectively, in Abcb1a/1b;Abcg2-/- mice, and to a lesser extent in single Abcb1a/1b- or Abcg2-deficient mice. The recovery of all active compounds in the small intestine content was profoundly reduced in Abcb1a/1b;Abcg2-/- mice, with smaller effects in single Abcb1a/1b-/- and Abcg2-/- mice. Our results indicate that Abcb1a/1b and Abcg2 cooperatively and profoundly limit the brain penetration of abemaciclib and its active metabolites, and likely also participate in their hepatobiliary or direct intestinal elimination. Moreover, transgenic human CYP3A4 drastically reduced the abemaciclib plasma AUC0-24 h and Cmax by 7.5- and 5.6-fold, respectively, relative to Cyp3a-/- mice. These insights may help to optimize the clinical development of abemaciclib, especially for the treatment of brain malignancies.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Aminopiridinas , Benzimidazóis , Citocromo P-450 CYP3A , Proteínas de Neoplasias , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/metabolismo , Aminopiridinas/farmacologia , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacologia , Encéfalo/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Cães , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Preparações Farmacêuticas/metabolismoRESUMO
Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.
Assuntos
Pirazóis , Pirimidinas , Animais , Cães , Canal de Potássio ERG1/metabolismo , Canais de Potássio Éter-A-Go-Go , Éteres , Humanos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Niraparib (Zejula), a selective oral PARP1/2 inhibitor registered for ovarian, fallopian tube, and primary peritoneal cancer treatment, is under investigation for other malignancies, including brain tumors. We explored the impact of the ABCB1 and ABCG2 multidrug efflux transporters, the OATP1A/1B uptake transporters, and the CYP3A drug-metabolizing complex on oral niraparib pharmacokinetics, using wild-type and genetically modified mouse and cell line models. In vitro, human ABCB1 and mouse Abcg2 transported niraparib moderately. Compared to wild-type mice, niraparib brain-to-plasma ratios were 6- to 7-fold increased in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- but not in single Abcg2-/- mice, while niraparib plasma exposure at later time points was â¼2-fold increased. Niraparib recovery in the small intestinal content was markedly reduced in the Abcb1a/1b-deficient strains. Pretreatment of wild-type mice with oral elacridar, an ABCB1/ABCG2 inhibitor, increased niraparib brain concentration and reduced small intestinal content recovery to levels observed in Abcb1a/1b;Abcg2-/- mice. Oatp1a/1b deletion did not significantly affect niraparib oral bioavailability or liver distribution but decreased metabolite M1 liver uptake. No significant effects of mouse Cyp3a ablation were observed, but overexpression of transgenic human CYP3A4 unexpectedly increased niraparib plasma exposure. Thus, Abcb1 deficiency markedly increased niraparib brain distribution and reduced its small intestinal content recovery, presumably through reduced biliary excretion and/or decreased direct intestinal excretion. Elacridar pretreatment inhibited both processes completely. Clinically, the negligible role of OATP1 and CYP3A could be advantageous for niraparib, diminishing drug-drug interaction or interindividual variation risks involving these proteins. These findings may support the further clinical development and application of niraparib.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Encéfalo/metabolismo , Indazóis/farmacocinética , Intestinos/metabolismo , Piperidinas/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Acridinas/farmacologia , Animais , Transporte Biológico , Citocromo P-450 CYP3A/fisiologia , Cães , Células Madin Darby de Rim Canino , Camundongos , Tetra-Hidroisoquinolinas/farmacologia , Distribuição TecidualRESUMO
Phosphodiesterase 7 (PDE7) is an enzyme responsible for the degradation of cyclic adenosine monophosphate (cAMP), an important cellular messenger. PDE7's role in neurotransmission, expression profile in the brain and the druggability of other phosphodiesterases have motivated the search for potent inhibitors to treat neurodegenerative and inflammatory diseases. Different heterocyclic compounds have been described over the years; among them, phenyl-2-thioxo-(1H)-quinazolin-4-one, called S14, has shown very promising results in different in vitro and in vivo studies. Recently, polymeric nanoparticles have been used as new formulations to target specific organs and produce controlled release of certain drugs. In this work, we describe poly(lactic-co-glycolic acid) (PLGA)-based polymeric nanoparticles loaded with S14. Their preparation, optimization, characterization and in vivo drug release profile are here presented as an effort to improve pharmacokinetic properties of this interesting PDE7 inhibitor.
Assuntos
Encéfalo/efeitos dos fármacos , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Quinazolinonas/química , Quinazolinonas/farmacocinética , Animais , Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 7/antagonistas & inibidores , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Estrutura Molecular , Nanopartículas/ultraestrutura , Tamanho da Partícula , PermeabilidadeRESUMO
The σ2 receptor (transmembrane protein 97), which is involved in cholesterol homeostasis, is of high relevance for neoplastic processes. The upregulated expression of σ2 receptors in cancer cells and tissue in combination with the antiproliferative potency of σ2 receptor ligands motivates the research in the field of σ2 receptors for the diagnosis and therapy of different types of cancer. Starting from the well described 2-(4-(1H-indol-1-yl)butyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline class of compounds, we synthesized a novel series of fluorinated derivatives bearing the F-atom at the aromatic indole/azaindole subunit. RM273 (2-[4-(6-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)butyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) was selected for labelling with 18F and evaluation regarding detection of σ2 receptors in the brain by positron emission tomography. Initial metabolism and biodistribution studies of [18F]RM273 in healthy mice revealed promising penetration of the radioligand into the brain. Preliminary in vitro autoradiography on brain cryosections of an orthotopic rat glioblastoma model proved the potential of the radioligand to detect the upregulation of σ2 receptors in glioblastoma cells compared to healthy brain tissue. The results indicate that the herein developed σ2 receptor ligand [18F]RM273 has potential to assess by non-invasive molecular imaging the correlation between the availability of σ2 receptors and properties of brain tumors such as tumor proliferation or resistance towards particular therapies.
Assuntos
Encéfalo/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/metabolismo , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/metabolismo , Receptores sigma/metabolismo , Animais , Feminino , Humanos , Ligantes , Masculino , Camundongos , Neoplasias/metabolismo , Ratos , Ratos Endogâmicos F344 , Tetra-Hidroisoquinolinas/química , Tetra-Hidroisoquinolinas/metabolismoRESUMO
A novel oxime platform, the substituted phenoxyalkyl pyridinium oximes (US patent 9,227,937), was invented at Mississippi State University with an objective of discovering a brain-penetrating antidote to highly potent organophosphate anticholinesterases, such as the nerve agents. The goal was reactivation of inhibited brain acetylcholinesterase to attenuate the organophosphate-induced hypercholinergic activity that results in glutamate-mediated excitotoxicity and neuropathology. The currently approved oxime antidote in the US, 2-PAM, cannot do this. Using highly relevant surrogates of sarin and VX that leave acetylcholinesterase phosphylated with the same chemical moiety as their respective nerve agents, in vitro screens and in vivo tests in rats were conducted to identify the most efficacious members of this platform. The most promising novel oximes provided 24-h survival of lethal level surrogate exposure better than 2-PAM in almost all cases, and two of the oximes shortened the time to cessation of seizure-like behavior while 2-PAM did not. The most promising novel oximes attenuated neuropathology as indicated by immunohistochemical stains for both glia and neurons, while 2-PAM did not protect either glia or neurons. These results strongly suggest that these novel oximes can function within the brain to protect it, and therefore show great promise as potential future nerve agent antidotes.
Assuntos
Encéfalo/efeitos dos fármacos , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/toxicidade , Reativadores da Colinesterase/farmacologia , Animais , Humanos , Compostos Organotiofosforados/toxicidade , Oximas/farmacologia , Sarina/toxicidadeRESUMO
PURPOSE: We characterized three canine P-gp (cP-gp) deficient MDCKII cell lines. Their relevance for identifying efflux transporter substrates and predicting limitation of brain penetration were evaluated. In addition, we discuss how compound selection can be done in drug discovery by using these cell systems. METHOD: hMDR1, hBCRP-transfected, and non-transfected MDCKII ZFN cells (all with knock-down of endogenous cP-gp) were used for measuring permeability and efflux ratios for substrates. The compounds were also tested in MDR1_Caco-2 and BCRP_Caco-2, each with a double knock-out of BCRP/MRP2 or MDR1/MRP2 transporters respectively. Efflux results were compared between the MDCK and Caco-2 models. Furthermore, in vitro MDR1_ZFN efflux data were correlated with in vivo unbound drug brain-to-plasma partition coefficient (Kp,uu). RESULTS: MDR1 and BCRP substrates are correctly classified and robust transporter affinities with control substrates are shown. Cell passage mildly influenced mRNA levels of transfected transporters, but the transporter activity was proven stable for several years. The MDCK and Caco-2 models were in high consensus classifying same efflux substrates. Approx. 80% of enlisted substances were correctly predicted with the MDR1_ZFN model for brain penetration. CONCLUSION: cP-gp deficient MDCKII ZFN models are reliable tools to identify MDR1 and BCRP substrates and useful for predicting efflux liability for brain penetration.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/deficiência , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Proteínas de Neoplasias/metabolismo , Farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Células CACO-2 , Permeabilidade da Membrana Celular , Dibenzocicloeptenos/farmacologia , Dicetopiperazinas/farmacologia , Cães , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Células Madin Darby de Rim Canino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Prazosina/farmacocinética , Quinidina/farmacocinética , Quinolinas/farmacologia , Especificidade por Substrato , TransfecçãoRESUMO
1. Withanolide A (WA), a major constituent phytochemical of the Ayurvedic herb Withania somnifera reportedly combats neurodegeneration in Alzheimer's disease and Parkinson's disease. But no study has yet reported the ability of WA in crossing the blood-brain barrier (BBB). The present study analyses the brain penetration ability of WA after intra-nasal administration and assesses its neuroprotective ability in cerebral ischemia-reperfusion injury in adult mice model.2. Brain penetration of WA after intranasal administration in cortex and cerebellum was assessed using HPLC-UV. Three different doses (1 mg/kg, 5 mg/kg and 10 mg/kg) of the phytochemical were used to study the neuroprotective ability of WA by evaluating the brain damage, changes in cerebral neurotransmitter levels and brain tissue morphology.3. Intranasal administration of the phytochemical facilitates its penetration in the cortex and cerebellum. Post-treatment with WA significantly reduced cerebral infarction, restored BBB disruption and cerebral oedema. The WA post-treatment also lowered the ischemia-induced elevated neurotransmitter and biochemical levels in brain compartments. The highest dose (10 mg/kg) of WA also markedly reduced the morphological damages, apoptotic and necrotic cell death in brain tissue occurring due to cerebral ischemia pathophysiology.4. Intra-nasal administration enables brain penetration of WA and allows the phytochemical to exert neuroprotective ability in the global cerebral ischemia model.
Assuntos
Fármacos Neuroprotetores/farmacologia , Vitanolídeos/farmacologia , Administração Intranasal , Animais , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Camundongos , Neuroproteção , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Vitanolídeos/administração & dosagem , Vitanolídeos/uso terapêuticoRESUMO
An expanded view of the substrate landscape of organic anion transporting polypeptide (OATP) 2B1 was pursued with the goal of understanding if the identification of novel in vitro substrates could shed additional light on the impact of OATP2B1 on intestinal absorption and brain penetration.To examine this hypothesis, a series of experiments measured the cellular accumulation of a diverse array of compounds. Representative angiotensin II receptor blockers (ARBs) and other compounds of interest were subsequently investigated for inhibition, time dependence, and kinetics.The study identified ARBs as a class of OATP2B1 substrates and found balsalazide, olsalzine, and gavestinel to be novel substrates of OATP2B1 too. Some compounds previously reported to be OATP2B1 substrates in the literature, aliskiren, erlotinib, montelukast, fexofenadine, and taurocholate could not be confirmed as substrates.Literature describing in vivo outcomes for OATP2B1 substrates, coproporphyrin III, ARBs, balsalazide, olsalzine, and gavestinel highlight the absence of a substantial impact of OATP2B1 on the oral absorption and/or brain penetration of OATP2B1 substrates. Suggestions of including OATP2B1 assessment as part of the drug approval process are likely premature and further mechanistic work with more robust OATP2B1 substrates, which may include some of those described here, is desirable.
Assuntos
Coproporfirinas/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Humanos , Absorção Intestinal , Terfenadina/análogos & derivadosRESUMO
Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction.The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites.Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways.
Assuntos
Benzamidas/farmacologia , Transtornos de Enxaqueca/fisiopatologia , Piperidinas/farmacologia , Piridinas/farmacologia , Receptores de Serotonina , Agonistas do Receptor de Serotonina/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Humanos , Neurônios/metabolismo , Gânglio Trigeminal/metabolismo , Gânglio Trigeminal/fisiopatologia , Triptaminas , Vasoconstrição/efeitos dos fármacos , Receptor 5-HT1F de SerotoninaRESUMO
Ribociclib is a CDK4/6 inhibitor recently approved for the treatment of some types of breast cancer in combination with an aromatase inhibitor. It is currently investigated in the clinic to treat other malignancies, including brain tumors. Using in vitro and genetically modified mouse models, we investigated the effect of the multidrug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing CYP3A enzymes on ribociclib pharmacokinetics and tissue distribution. In vitro, ribociclib was avidly transported by human ABCB1, but not by human ABCG2 and only modestly by mouse Abcg2. Upon oral administration at 20 mg/kg, the plasma AUC0-24h of ribociclib was increased by 2.3-fold, and its terminal elimination was delayed in Abcb1a/1b-/-;Abcg2-/- compared to wild-type mice. The brain-to-plasma ratios of ribociclib were increased by at least 23-fold relative to wild-type mice in Abcb1a/1b-/-;Abcg2-/- and Abc1a/1b-/- mice, but not noticeably in Abcg2-/- mice. Oral coadministration of elacridar, an ABCB1 and ABCG2 inhibitor, increased the brain penetration of ribociclib in wild-type mice to the same level as seen in Abcb1a/1b-/-;Abcg2-/- mice. Plasma exposure of ribociclib further decreased by 3.8-fold when transgenic human CYP3A4 was overexpressed in Cyp3a-deficient mice. Ribociclib penetration into the brain is thus drastically limited by ABCB1 in the blood-brain barrier, but coadministration of elacridar can fully reverse this process. Moreover, human CYP3A4 can extensively metabolize ribociclib and strongly restrict its oral bioavailability. The insights obtained from this study may be useful to further optimize the clinical application of ribociclib, especially for the treatment of (metastatic) brain tumors.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aminopiridinas/administração & dosagem , Aminopiridinas/farmacocinética , Barreira Hematoencefálica/efeitos dos fármacos , Citocromo P-450 CYP3A/metabolismo , Purinas/administração & dosagem , Purinas/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Acridinas/farmacologia , Administração Oral , Aminopiridinas/metabolismo , Animais , Disponibilidade Biológica , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Cães , Feminino , Humanos , Células Madin Darby de Rim Canino , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Purinas/metabolismo , Tetra-Hidroisoquinolinas/farmacologia , Distribuição Tecidual , Transdução GenéticaRESUMO
Huntington's disease (HD) is a neurodegenerative disease caused by polyglutamine expansion in the huntingtin protein. For drug candidates targeting HD, the ability to cross the blood-brain barrier (BBB) and reach the site of action in the central nervous system (CNS) is crucial for achieving pharmacological activity. To assess the permeability of selected compounds across the BBB, we utilized a two-dimensional model composed of primary porcine brain endothelial cells and rat astrocytes. Our objective was to use this in vitro model to rank and prioritize compounds for in vivo pharmacokinetic and brain penetration studies. The model was first characterized using a set of validation markers chosen based on their functional importance at the BBB. It was shown to fulfill the major BBB characteristics, including functional tight junctions, high transendothelial electrical resistance, expression, and activity of influx and efflux transporters. The in vitro permeability of 54 structurally diverse known compounds was determined and shown to have a good correlation with the in situ brain perfusion data in rodents. We used this model to investigate the BBB permeability of a series of new HD compounds from different chemical classes, and we found a good correlation with in vivo brain permeation, demonstrating the usefulness of the in vitro model for optimizing CNS drug properties and for guiding the selection of lead compounds in a drug discovery setting.
Assuntos
Barreira Hematoencefálica/metabolismo , Fármacos do Sistema Nervoso Central/uso terapêutico , Descoberta de Drogas/métodos , Doença de Huntington/tratamento farmacológico , Modelos Biológicos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Astrócitos/metabolismo , Permeabilidade Capilar/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Técnicas de Cocultura , Impedância Elétrica , Células Endoteliais/metabolismo , Permeabilidade , Ratos , Ratos Sprague-Dawley , Proteínas Carreadoras de Solutos/metabolismo , Suínos , Junções Íntimas/metabolismoRESUMO
The discovery of disease-modifying therapies for Parkinson's Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.
Assuntos
Indazóis/química , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Descoberta de Drogas , Ligação de HidrogênioRESUMO
CDK4 and CDK6 are kinases with similar sequences that regulate cell cycle progression and are validated targets in the treatment of cancer. Glioblastoma is characterized by a high frequency of CDKN2A/CCND2/CDK4/CDK6 pathway dysregulation, making dual inhibition of CDK4 and CDK6 an attractive therapeutic approach for this disease. Abemaciclib, ribociclib, and palbociclib are approved CDK4/6 inhibitors for the treatment of HR+/HER2- breast cancer, but these drugs are not expected to show strong activity in brain tumors due to poor blood brain barrier penetration. Herein, we report the identification of a brain-penetrant CDK4/6 inhibitor derived from a literature molecule with low molecular weight and topological polar surface area (MWâ¯=â¯285 and TPSAâ¯=â¯66â¯Å2), but lacking the CDK2/1 selectivity profile due to the absence of a basic amine. Removal of a hydrogen bond donor via cyclization of the pyrazole allowed for the introduction of basic and semi-basic amines, while maintaining in many cases efflux ratios reasonable for a CNS program. Ultimately, a basic spiroazetidine (cpKaâ¯=â¯8.8) was identified that afforded acceptable selectivity over anti-target CDK1 while maintaining brain-penetration in vivo (mouse Kp,uuâ¯=â¯0.20-0.59). To probe the potency and selectivity, our lead compound was evaluated in a panel of glioblastoma cell lines. Potency comparable to abemaciclib was observed in Rb-wild type lines U87MG, DBTRG-05MG, A172, and T98G, while Rb-deficient cell lines SF539 and M059J exhibited a lack of sensitivity.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desenho de Fármacos , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/metabolismo , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Células MCF-7 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-AtividadeRESUMO
Phosphodiesterase 10A (PDE10A) inhibitors were designed and synthesized based on the dihydro-imidazobenzimidazole scaffold. Compound 5a showed moderate inhibitory activity and good permeability, but unfavorable high P-glycoprotein (P-gp) liability for brain penetration. We performed an optimization study to improve both the P-gp efflux ratio and PDE10A inhibitory activity. As a result, 6d was identified with improved P-gp liability and high PDE10A inhibitory activity. Compound 6d also showed satisfactory brain penetration, suppressed phencyclidine-induced hyperlocomotion and improved MK-801-induced working memory deficit.
Assuntos
Inibidores de Fosfodiesterase/uso terapêutico , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-AtividadeRESUMO
1. The present study is designed to investigate the brain distribution and plasma pharmacokinetics profiles of chlorogenic acid (CGA) after intranasal administration in Charles-Foster rats to evaluate whether the CGA molecules are transported directly via the nose-to-brain path. 2. The CGA is administered intravenously (IV) and intranasally (IN) at the dose of 10 mg/kg. Further, its concentration in the plasma, cerebrospinal fluid (CSF) and the whole brain is analyzed by HPLC-UV method. 3. The study observes that CGA is rapidly absorbed in plasma with tmax of 1 min similar to IV route after IN administration. The peak plasma concentration and AUC0-24 are higher by 3.5 and 4.0 times respectively in IV administration, compared to IN delivery that represents the significant less systemic exposure of CGA in IN route. 4. However, the concentration of CGA in the brain is 4, 6.5, 5.3, 5.2 and 4.5 times higher at 30, 60, 120, 240 and 360 min, respectively in IN administration compared to IV administration. The exposure of CGA in the brain after IN administration (AUCbrain, IN) was significantly greater (4 times) as compared to the exposure of CGA in the brain (AUCbrain, IV) after IV administration reflecting significant brain uptake of CGA through nasal route. Therefore, IN delivery of CGA can be a promising approach for the treatment of stroke and neurodegenerative disorders.