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The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and drug-drug interactions (DDIs) via modulation of transporters could lead to clinical adverse events. Organic anion-transporting polypeptide 1B (OATP1B) are liver specific uptake transporters in humans that can transport a broad range of substrates, including statins. It is a challenge to predict OATP1B-mediated DDIs using preclinical animal models because of species differences in substrate specificity and abundance levels of transporters. PXB-mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug metabolism and pharmacokinetics studies in drug discovery. In the present study, we measured the exposure increases (blood AUC and Cmax) of ten OATP1B substrates in PXB-mice upon co-administration with rifampin, a potent OATP1B specific inhibitor. These data in PXB-mice were then compared with the observed DDIs between OATP1B substrates and single-dose rifampin in humans. Our findings suggest that the DDIs between OATP1B substrates and rifampin in PXB-mouse are comparable with the observed DDIs in the clinic. Since most OATP1B substrates are metabolized by CYPs and/or are substrates of P-glycoprotein (P-gp), we further validated the utility of PXB-mice to predict complex DDIs involving inhibition of OATP1B, CYPs and P-gp using CsA and gemfibrozil as perpetrators. Overall, the data support that the chimeric mice with humanized livers could be a useful tool for the prediction of hepatic OATP1B-mediated DDIs in humans. Significance Statement The ability of PXB-mouse with humanized liver to predict OATP1B-mediated drug-drug interactions (DDIs) in humans was evaluated. The plasma exposure increases of ten OATP1B substrates with rifampin, an OATP1B inhibitor, in PXB-mice have a good correlation with those observed in humans. More importantly, PXB-mice can predict complex DDIs including inhibition of OATP1B, CYPs and P-gp in humans. PXB-mice are a promising useful tool to assess OATP1B-mediated clinical DDIs.
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Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).
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Melanoma , Neoplasias de la Úvea , Adulto , Humanos , Subunidades alfa de la Proteína de Unión al GTP/genética , Subunidades alfa de la Proteína de Unión al GTP/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias de la Úvea/tratamiento farmacológico , Neoplasias de la Úvea/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , MutaciónRESUMEN
OBJECTIVE: Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by autosomal-dominant pathogenic variants in either the TSC1 or TSC2 gene, and it is characterized by hamartomas in multiple organs, such as skin, kidney, lung, and brain. These changes can result in epilepsy, learning disabilities, and behavioral complications, among others. The mechanistic link between TSC and the mechanistic target of the rapamycin (mTOR) pathway is well established, thus mTOR inhibitors can potentially be used to treat the clinical manifestations of the disorder, including epilepsy. METHODS: In this study, we tested the efficacy of a novel mTOR catalytic inhibitor (here named Tool Compound 1 or TC1) previously reported to be more brain-penetrant compared with other mTOR inhibitors. Using a well-characterized hypomorphic Tsc2 mouse model, which displays a translationally relevant seizure phenotype, we tested the efficacy of TC1. RESULTS: Our results show that chronic treatment with this novel mTOR catalytic inhibitor (TC1), which affects both the mTORC1 and mTORC2 signaling complexes, reduces seizure burden, and extends the survival of Tsc2 hypomorphic mice, restoring species typical weight gain over development. INTERPRETATION: Novel mTOR catalytic inhibitor TC1 exhibits a promising therapeutic option in the treatment of TSC.
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Epilepsia , Esclerosis Tuberosa , Ratones , Animales , Esclerosis Tuberosa/tratamiento farmacológico , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/patología , Proteínas Supresoras de Tumor/genética , Inhibidores mTOR , Serina-Treonina Quinasas TOR/genética , Modelos Animales de Enfermedad , Epilepsia/genética , Convulsiones/tratamiento farmacológicoRESUMEN
The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor (1) that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the Tsc1 gene. However, 1 showed the risk of genotoxicity in vitro. Through structure-activity relationship (SAR) optimization, we identified compounds 9 and 11 without genotoxicity risk. In neuronal cell-based models of mTOR hyperactivity, both corrected aberrant mTOR activity and significantly improved the survival rate of mice in the Tsc1 gene knockout model. Unfortunately, 9 and 11 showed limited oral exposures in higher species and dose-limiting toxicities in cynomolgus macaque, respectively. However, they remain optimal tools to explore mTOR hyperactivity in CNS disease models.
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Inhibidores mTOR , Sirolimus , Ratones , Animales , Síndrome , Sistema Nervioso Central/metabolismo , Encéfalo/metabolismo , Serina-Treonina Quinasas TOR , Adenosina TrifosfatoRESUMEN
RATIONALE: Osteoporotic vertebral compression fracture (OVCF) accompanying huge spinal epidural hematoma (SEH) is fairly rare. The aim of this report is to investigate the management strategies and treatment outcomes of OVCF accompanying SEH. PATIENT CONCERNS: An 89-year-old female patient was admitted to hospital because of severe back pain and numbness of both lower limbs after a slight fall. The magnetic resonance imaging examination of the patient showed a fresh compression fracture at L2 accompanying a large dorsal SEH which extended from the T12 to L3 and deformed the spinal cord. DIAGNOSIS: The patient was diagnosed with OVCF accompanying SEH. INTERVENTIONS: Given mild neurologic deficits, the hematoma was not treated, and the patient underwent percutaneous vertebroplasty (PVP) only. OUTCOMES: After the procedure, immediate pain relief was achieved and the numbness of both lower limbs disappeared 3âdays later. Three months after the procedure, the follow-up magnetic resonance imaging revealed a complete resolution of the hematoma. LESSONS: OVCF accompanying SEH is fairly rare, and the exact pathophysiological mechanisms are still not clear. In selected patients without or with only slight neurologic symptoms, it is reasonable to perform PVP alone in OVCF accompanying SEH. Moreover, intravertebral stability after PVP might have played a role in spontaneous resolution of SEH.
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Fracturas por Compresión , Hematoma Espinal Epidural , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Vertebroplastia , Anciano de 80 o más Años , Femenino , Fracturas por Compresión/complicaciones , Fracturas por Compresión/diagnóstico por imagen , Fracturas por Compresión/cirugía , Hematoma Espinal Epidural/complicaciones , Hematoma Espinal Epidural/diagnóstico por imagen , Hematoma Espinal Epidural/cirugía , Humanos , Hipoestesia , Fracturas Osteoporóticas/complicaciones , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/cirugía , Fracturas de la Columna Vertebral/complicaciones , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/cirugía , Resultado del Tratamiento , Vertebroplastia/métodosRESUMEN
Cervical sagittal balance is an important evaluation index of cervical physiological function and surgical efficacy. Subaxial kyphosis after atlantoaxial fusion is negatively associated with worse clinical outcomes and higher incidence of lower cervical disk degeneration. OBJECTIVES: This study aimed to confirm the factors that influence subaxial lordosis loss after posterior atlantoaxial fusion. METHODS: We performed a retrospective review of all patients following posterior C1-C2 fusion for atlantoaxial dislocation between January 2015 and December 2017. All charts, records, and imaging studies were reviewed for each case, and preoperative, immediate postoperative, and final follow-up plain films were evaluated. Comparing final follow-up and preoperative C2-C7 angle, patients were divided into two groups for further comparison: subaxial lordosis loss group and subaxial lordosis increase group. RESULTS: A total of 18 patients were included in the review, with an average radiographic follow-up of 8.4 ± 3.7 months (range 6-17 months). Subaxial lordosis loss was observed in 5 cases (27.8%) at the final follow-up, whereas 13 cases had an increase in subaxial lordosis. The cervical sagittal parameters of preoperative and final follow-up between two groups were compared, the preoperative C2-C7 angle of the subaxial lordosis loss group was bigger than the subaxial lordosis increase group (27.6° ± 10.5° vs 10.5° ± 10.5°, P < 0.05), but there was no statistical difference in other parameters. Univariate chi-square analysis showed that reduction in subaxial lordosis after posterior atlantoaxial fusion was associated with preoperative C2-C7 angle ≥ 20° (χ2 = 4.923, P = 0.026). However, Logistic regression analysis showed that the preoperative C2-C7 angle ≥ 20° was not an independent risk factor (OR = 0.147, P = 0.225). CONCLUSION: Our study demonstrates that subaxial lordosis loss may occur after posterior atlantoaxial fusion, and preoperative C2-C7 angle ≥ 20° was a risk factor of postoperative loss of subaxial lordosis.
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Articulación Atlantoaxoidea , Lordosis , Fusión Vertebral , Articulación Atlantoaxoidea/anomalías , Articulación Atlantoaxoidea/diagnóstico por imagen , Articulación Atlantoaxoidea/cirugía , Vértebras Cervicales/diagnóstico por imagen , Vértebras Cervicales/cirugía , Anomalías Congénitas , Humanos , Lordosis/diagnóstico por imagen , Lordosis/etiología , Lordosis/cirugía , Estudios Retrospectivos , Fusión Vertebral/efectos adversos , Fusión Vertebral/métodosRESUMEN
RATIONALE: The thoracic spine is stabilized in the anteroposterior direction by the rib cage and the facet joints, thus thoracic degenerative spondylolisthesis is very uncommon. Here, we report a rare case of thoracic degenerative spondylolisthesis in which the lower thoracic region was the only region involved. PATIENT CONCERNS: We present the case of a 56-year-old Chinese female who suffered from thoracic degenerative spondylolisthesis. She had a 2-year history of gait disturbance and bilateral lower-extremity numbness. The initial imaging examinations revealed Grade I anterior spondylolisthesis and severe cord compression, as well as bilateral facet joint osteoarthritis at T11/12. DIAGNOSIS: The patient was diagnosed with thoracic degenerative spondylolisthesis-associated myelopathy. INTERVENTIONS: She underwent a posterior decompression with transforaminal thoracic interbody fusion (TTIF) at T11/12. OUTCOMES: The patient recovered well after the operation, and MRI at 12-month follow-up revealed that spinal cord compression was relieved and high signal intensity in T2-weighted image was improved. LESSONS: To the best of our knowledge, this is the first reported case of thoracic degenerative spondylolisthesis in which the lower thoracic region was the only region involved. Disruption of joint capsule, instability with micromotion, and degenerative disc may contribute to this rare disease. Posterior decompression with posterolateral fusion or TTIF were the main treatment modalities, however, TTIF has its unique advantages because of sufficient decompression, immediate stability and high fusion rate.
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Espondilolistesis/patología , Espondilolistesis/cirugía , Vértebras Torácicas/patología , Vértebras Torácicas/cirugía , Descompresión Quirúrgica , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Extremidad Inferior , Imagen por Resonancia Magnética , Persona de Mediana Edad , Osteoartritis/diagnóstico por imagen , Osteoartritis/etiología , Parestesia/etiología , Compresión de la Médula Espinal/diagnóstico por imagen , Compresión de la Médula Espinal/etiología , Fusión Vertebral , Espondilolistesis/complicaciones , Espondilolistesis/diagnóstico por imagen , Vértebras Torácicas/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Percutaneous endoscopic lumbar discectomy (PELD) has routinely performed in recent years for lumbar disc herniation because of the advances in technology of minimally invasive spine surgery. Two common operating routes for PELD have been introduced in the literature: transforaminal approach (TA) and interlaminar approach (IA). The purpose of our current retrospective clinical trial was to study whether the effect of IA-PELD is better than TA-PELD in the incidence of complications and clinical prognosis scores in the patients with L5-S1 lumbar disc herniation. METHODS: Our present research was approved by the institutional review board in the Second Hospital of Nanjing. All the patients offered the informed consent. All the procedures containing human participants were conducted on the basis of the Helsinki Declaration. A retrospective analysis was implemented on 126 patients with L5-S1 disc herniated radiculopathy from March 2016 to March 2018, who were treated with the PELD utilizing the IA technique or the TA technique. Relevant data, such as the patients demographics, surgical duration, length of hospital stay, hospitalization expenses, complications were recorded. In our work, the outcomes of patients were determined at baseline, 6 months, 12 months, and 24 months after treatment. The measure of primary outcome was Oswestry Disability Index score. The other outcomes measured were Numeric Rating Scale pain scale, surgical duration, length of hospital stay, and complications. The software of SPSS Version 22.0 (IBM Corporation, Armonk, NY) was applied for the analysis of all the statistical data. When P value <.05, it was considered to be significant in statistics. RESULTS: This protocol will provide a solid theoretical basis for exploring which PELD approach is better in treatment of lumbar disc herniation. TRIAL REGISTRATION: This study protocol was registered in Research Registry (researchregistry5988).
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Discectomía Percutánea/métodos , Endoscopía/métodos , Desplazamiento del Disco Intervertebral/cirugía , Vértebras Lumbares/cirugía , Radiculopatía/cirugía , Adulto , Evaluación de la Discapacidad , Endoscopía/efectos adversos , Estudios de Evaluación como Asunto , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Dolor Postoperatorio/epidemiología , Dolor Postoperatorio/etiología , Proyectos de Investigación , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.
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Composición de Medicamentos , Evaluación Preclínica de Medicamentos , Excipientes/farmacología , Animales , Evaluación Preclínica de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/normas , Excipientes/efectos adversos , Humanos , Terapia Molecular DirigidaRESUMEN
The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1ß, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.
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Factor XIa/antagonistas & inhibidores , Factor XIa/genética , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/química , Administración Oral , Secuencia de Aminoácidos , Animales , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos/métodos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Inhibition of neprilysin (NEP) is widely studied as a therapeutic target for the treatment of hypertension, heart failure, and kidney disease. Sacubitril/valsartan (LCZ696) is a drug approved to reduce the risk of cardiovascular death in heart failure patients with reduced ejection fraction. LBQ657 is the active metabolite of sacubitril and an inhibitor of NEP. Previously, we have reported the crystal structure of NEP bound with LBQ657, whereby we noted the presence of a subsite in S1' that has not been explored before. We were also intrigued by the zinc coordination made by one of the carboxylic acids of LBQ657, leading us to explore alternative linkers to efficiently engage zinc for NEP inhibition. Structure-guided design culminated in the synthesis of selective, orally bioavailable, and subnanomolar inhibitors of NEP. A 17-fold boost in biochemical potency was observed upon addition of a chlorine atom that occupied the newly found subsite in S1'. We report herein the discovery and preclinical profiling of compound 13, which paved the path to our clinical candidate.
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Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.
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Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Convulsiones/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Tiazoles/uso terapéutico , Animales , Anticonvulsivantes/metabolismo , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Sitios de Unión , Encéfalo/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas , Serina-Treonina Quinasas TOR/química , Serina-Treonina Quinasas TOR/metabolismo , Tiazoles/metabolismo , Tiazoles/farmacocinética , Proteína 1 del Complejo de la Esclerosis Tuberosa/genéticaRESUMEN
Mutant isocitrate dehydrogenase 1 (IDH1) is an attractive therapeutic target for the treatment of various cancers such as AML, glioma, and glioblastoma. We have evaluated 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors that bind to an allosteric, induced pocket of IDH1R132H. This Letter describes SAR exploration focused on improving both the in vitro and in vivo metabolic stability of the compounds, leading to the identification of 19 as a potent and selective mutant IDH1 inhibitor that has demonstrated brain penetration and excellent oral bioavailability in rodents. In a preclinical patient-derived IDH1 mutant xenograft tumor model study, 19 efficiently inhibited the production of the biomarker 2-HG.
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OBJECTIVE: To study the distribution of bone cement in unilateral puncture percutaneous vertebroplasty (PVP). MATERIAL AND METHODS: A total of 64 patients with osteoporotic vertebral compression fractures (OVCF) who underwent unilateral PVP were included in this study. The vertebral body was longitudinally divided into four equal parts. The intermediate layer between each part was representative of the part and there were four layers in total. Each layer was divided into 4 regions a, b, c, and d by the crossed lines at the center of the vertebral body. Region c was the first half of the puncture side and region d was the second half of the puncture side. Region a was the first half of the opposite side, and b was the second half of the opposite side. Bone cement filling areas in the four layers and the four regions of each layer were compared. RESULTS: There were significant differences in visual analogue scale (VAS) scores before and after surgery (Pâ¯< 0.05). Variance analysis indicated that the bone cement filling ratio of the region b in each layer was significantly lower than the other three regions, and that the bone cement filling ratio of region a was equal to that of the region d. CONCLUSION: Unilateral puncture PVP can reduce VAS scores, and plays a role in reducing pain. The bone cement showed a regular distribution.
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Cementos para Huesos , Fracturas por Compresión/cirugía , Fracturas Osteoporóticas/cirugía , Punciones , Fracturas de la Columna Vertebral/cirugía , Vertebroplastia/métodos , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Escala Visual AnalógicaRESUMEN
Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
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Herein we describe the discovery and characterization of a novel, piperidine-based inhibitor of cholesteryl ester transfer protein (CETP) with a core structure distinct from other reported CETP inhibitors. A versatile synthesis starting from 4-methoxypyridine enabled an efficient exploration of the SAR, giving a lead molecule with potent CETP inhibition in human plasma. The subsequent optimization focused on improvement of pharmacokinetics and mitigation of off-target liabilities, such as CYP inhibition, whose improvement correlated with increased lipophilic efficiency. The effort led to the identification of an achiral, carboxylic acid-bearing compound 16 (TAP311) with excellent pharmacokinetics in rats and robust efficacy in hamsters. Compared to anacetrapib, the compound showed substantially reduced lipophilicity, had only modest distribution into adipose tissue, and retained potency in hypertriglyceridemic plasma in vitro and in vivo. Furthermore, in contrast to torcetrapib, the compound did not increase aldosterone secretion in human adrenocortical carcinoma cells nor in chronically cannulated rats. On the basis of its preclinical efficacy and safety profile, the compound was advanced into clinical trials.
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Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Hipertrigliceridemia/sangre , Piperidinas/farmacología , Anciano , Animales , Embrión de Pollo , Humanos , Masculino , Mesocricetus , Piperidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Surface sampling micro liquid chromatography tandem mass spectrometry (SSµLC-MS/MS) was explored as a quantitative tissue distribution technique for probing compound properties in drug discovery. A method was developed for creating standard curves using surrogate tissue sections from blank tissue homogenate spiked with compounds. The resulting standard curves showed good linearity and high sensitivity. The accuracy and precision of standards met acceptance criteria of ±30%. A new approach was proposed based on an experimental and mathematical method for tissue extraction efficiency evaluation by means of consecutively sampling a location on tissue twice by SSµLC-MS/MS. The observed extraction efficiency ranged from 69% to 82% with acceptable variation for the test compounds. Good agreement in extraction efficiency was observed between surrogate tissue sections and incurred tissue sections. This method was successfully applied to two case studies in which tissue distribution was instrumental in advancing project teams' understanding of compound properties.
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Descubrimiento de Drogas , Preparaciones Farmacéuticas/análisis , Cromatografía Liquida/instrumentación , Propiedades de Superficie , Espectrometría de Masas en Tándem/instrumentaciónRESUMEN
We present a systematic evaluation of the Wajima superpositioning method to estimate the human intravenous (i.v.) pharmacokinetic (PK) profile based on a set of 54 marketed drugs with diverse structure and range of physicochemical properties. We illustrate the use of average of "best methods" for the prediction of clearance (CL) and volume of distribution at steady state (VDss) as described in our earlier work (Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):178-191; Lombardo F, Waters NJ, Argikar UA, et al. J Clin Pharmacol. 2013;53(2):167-177). These methods provided much more accurate prediction of human PK parameters, yielding 88% and 70% of the prediction within 2-fold error for VDss and CL, respectively. The prediction of human i.v. profile using Wajima superpositioning of rat, dog, and monkey time-concentration profiles was tested against the observed human i.v. PK using fold error statistics. The results showed that 63% of the compounds yielded a geometric mean of fold error below 2-fold, and an additional 19% yielded a geometric mean of fold error between 2- and 3-fold, leaving only 18% of the compounds with a relatively poor prediction. Our results showed that good superposition was observed in any case, demonstrating the predictive value of the Wajima approach, and that the cause of poor prediction of human i.v. profile was mainly due to the poorly predicted CL value, while VDss prediction had a minor impact on the accuracy of human i.v. profile prediction.
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Preparaciones Farmacéuticas/sangre , Preparaciones Farmacéuticas/metabolismo , Administración Intravenosa/métodos , Animales , Perros , Haplorrinos , Humanos , Ratas , Análisis de Regresión , Especificidad de la EspecieRESUMEN
Human clinical studies conducted with LCI699 established aldosterone synthase (CYP11B2) inhibition as a promising novel mechanism to lower arterial blood pressure. However, LCI699's low CYP11B1/CYP11B2 selectivity resulted in blunting of adrenocorticotropic hormone-stimulated cortisol secretion. This property of LCI699 prompted its development in Cushing's disease, but limited more extensive clinical studies in hypertensive populations, and provided an impetus for the search for cortisol-sparing CYP11B2 inhibitors. This paper summarizes the discovery, pharmacokinetics, and pharmacodynamic data in preclinical species and human subjects of the selective CYP11B2 inhibitor 8.
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Citocromo P-450 CYP11B2/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Indoles/química , Antagonistas de Receptores de Mineralocorticoides/química , Piridinas/química , Sulfonamidas/química , Aldosterona/metabolismo , Animales , Citocromo P-450 CYP11B2/metabolismo , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Halogenación , Haplorrinos , Humanos , Hipertensión/tratamiento farmacológico , Indoles/farmacocinética , Indoles/farmacología , Metilación , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Antagonistas de Receptores de Mineralocorticoides/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
CYP11B2, the aldosterone synthase, and CYP11B1, the cortisol synthase, are two highly homologous enzymes implicated in a range of cardiovascular and metabolic diseases. We have previously reported the discovery of LCI699, a dual CYP11B2 and CYP11B1 inhibitor that has provided clinical validation for the lowering of plasma aldosterone as a viable approach to modulate blood pressure in humans, as well normalization of urinary cortisol in Cushing's disease patients. We now report novel series of aldosterone synthase inhibitors with single-digit nanomolar cellular potency and excellent physicochemical properties. Structure-activity relationships and optimization of their oral bioavailability are presented. An illustration of the impact of the age of preclinical models on pharmacokinetic properties is also highlighted. Similar biochemical potency was generally observed against CYP11B2 and CYP11B1, although emerging structure-selectivity relationships were noted leading to more CYP11B1-selective analogs.