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INTRODUCTION: To determine the risk factors of hyperlactatemia in pulmonary endarterectomy (PEA) surgery and assess whether elevated blood lactate levels are associated with adverse outcomes. METHODS: In this retrospective observational study, a total of 111 consecutive patients who underwent PEA for chronic thromboembolic pulmonary hypertension at the XXX Hospital between December 2016 and January 2022 were included. We retrospectively evaluated arterial blood samples analyzed intraoperatively. The pre- and intraoperative risk factors for hyperlactatemia and the postoperative outcomes were recorded. RESULTS: Lactate levels gradually increased during surgery. The optimal cut-off lactate level for major postoperative complications, calculated using receiver operating characteristic analysis, was 7.0 mmol/L. Deep hypothermic circulatory arrest (DHCA) duration, nadir hematocrit, and preoperative pulmonary vascular resistance were risk factors for lactate levels >7 mmol/L. Moreover, the intraoperative peak lactate level during PEA under DHCA was found to be a statistically significant predictor of major complications being associated with longer mechanical ventilation time (r = 0.294; p = .003) and intensive care unit length of stay (r = 0.327; p = .001). CONCLUSIONS: Deep hypothermic circulatory arrest duration, nadir hematocrit, and preoperative pulmonary vascular resistance were associated with hyperlactatemia. Increased lactate levels were independent predictors of longer mechanical ventilation time, intensive care unit length of stay, and major complications.
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Objective: To investigate the incidence, risk factors, and outcomes of hyperlactatemia after pulmonary endarterectomy (PEA) under deep hypothermic circulatory arrest (DHCA). Methods: From December 2016 to January 2022, patients receiving PEA in China-Japan Friendship Hospital were enrolled in the study. Arterial blood samples were analyzed intraoperatively. Multivariate logistic regression analysis was performed to identify the predictors of intraoperative lactate elevation as well as major factors influencing the clinical outcome of the surgery. Results: A total of 110 patients (69 males and 41 females) were enrolled, aged (50.6±12.8) years. Receiver operating characteristic curve yielded an optimal cut-off lactate level of 7 mmol/L for predicting major postoperative complications (re-operation, re-intubation, postoperative renal failure requiring renal replacement therapy, wound infection, stroke, atrial fibrillation, and perioperative extracorporeal membrane oxygenation usage within 48 hours after surgery). Thirty-nine patients (35.5%) had an intraoperative peak arterial lactate level of≥7 mmol/L. According to intraoperative peak arterial lactate level, the patients were divided into two groups (<7 mmol/L and≥7 mmol/L). There were no statistically significant differences in age, sex and body mass index between the two groups (all P>0.05). Intraoperative peak lactate level was associated with prolonged mechanical ventilation time (r=0.262, P=0.008) and intensive care unit length of stay (r=0.304, P=0.002). Multivariate logistic regression analysis identified three key variables associated with lactate level≥7 mmol/L: DHCA duration (OR=1.186, 95%CI: 1.027-1.370, P=0.020), nadir hematocrit (HCT) (OR=0.580, 95%CI: 0.341-0.988, P=0.045) and preoperative pulmonary vascular resistance (PVR) (OR=1.096, 95%CI: 1.020-1.177, P=0.012). Patients with lactate≥7 mmol/L carried a higher rate of major complications (P=0.001). For patients with lactate≥7 mmol/L, 41.0% (16 out of 39 cases) had major complications, while for patients with lactate<7 mmol/L, only 14.1% (10 out of 71) had major complications. There was no statistically significant difference in mortality (8.5% vs 10.3%, P=0.753) between patients with different lactate levels. Moreover, intraoperative peak lactate level was a predictor of postoperative combined morbidity (OR=1.625, 95%CI: 1.176-2.245, P=0.003). Conclusion: High intraoperative lactate levels are associated with higher preoperative PVR, lower nadir HCT, and longer DHCA duration. Intraoperative lactate levels are independently associated with increased combined morbidity.
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Hiperlactatemia , Masculino , Femenino , Humanos , Paro Circulatorio Inducido por Hipotermia Profunda , Pronóstico , Factores de Riesgo , Ácido Láctico , Endarterectomía , Estudios RetrospectivosRESUMEN
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled-related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.
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Hipertensión Pulmonar , Músculo Liso Vascular , Desdiferenciación Celular , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Células Cultivadas , Humanos , Hipertensión Pulmonar/metabolismo , Dinámicas Mitocondriales/fisiología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Remodelación Vascular/genética , Proteínas Wnt/metabolismoRESUMEN
Atherosclerosis is a significant cardiovascular burden and a leading cause of death worldwide, recognized as a chronic sterile inflammatory disease. Pyroptosis is a novel proinflammatory regulated cell death, characterized by cell swelling, plasma membrane bubbling, and robust release of proinflammatory cytokines (such as interleukin IL-1ß and IL-18). Mounting studies have addressed the crucial contribution of pyroptosis to atherosclerosis and clarified the candidate therapeutic agents targeting pyroptosis for atherosclerosis. Herein, we review the initial characterization of pyroptosis, the detailed mechanisms of pyroptosis, current evidence about pyroptosis and atherosclerosis, and potential therapeutic strategies that target pyroptosis in the development of atherosclerosis.
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Antiinflamatorios/uso terapéutico , Arterias/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Citocinas/metabolismo , Inflamasomas/metabolismo , Mediadores de Inflamación/metabolismo , Piroptosis/efectos de los fármacos , Animales , Arterias/metabolismo , Arterias/patología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Transducción de SeñalRESUMEN
A series of IDO1 inhibitors containing a decahydroquinoline, decahydro-1,6-naphthyridine, or octahydro-1H-pyrrolo[3,2-c]pyridine scaffold were identified with good cellular and human whole blood activity against IDO1. These inhibitors contain multiple chiral centers and all diastereomers were separated. The absolute stereochemistry of each isomers were not determined. Compounds 15 and 27 stood out as leads due to their good cellular as well as human whole blood IDO1 inhibition activity, low unbound clearance, and reasonable mean residence time in rat cassette PK studies.
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Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Naftiridinas/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Animales , Dominio Catalítico , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Células HeLa , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/química , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Simulación del Acoplamiento Molecular , Naftiridinas/síntesis química , Naftiridinas/metabolismo , Naftiridinas/farmacocinética , Pirroles/síntesis química , Pirroles/metabolismo , Pirroles/farmacocinética , Quinolinas/síntesis química , Quinolinas/metabolismo , Quinolinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.
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Compuestos Aza/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Indoles/farmacología , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Indoles/síntesis química , Indoles/química , Masculino , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
After decades of intense effort, immune checkpoint inhibitors have been conclusively demonstrated to be effective in cancer treatments and thus are revolutionizing the concepts in the treatment of cancers. Immuno-oncology has arrived and will play a key role in cancer treatment in the foreseeable future. However, efforts to find novel methods to improve the immune response to cancer have not ceased. Small-molecule approaches offer inherent advantages over biologic immunotherapies since they can cross cell membranes, penetrate into tumor tissue and tumor microenvironment more easily, and are amenable to be finely controlled than biological agents, which may help reduce immune-related adverse events seen with biologic therapies and provide more flexibility for the combination use with other therapies and superior clinical benefit. On the one hand, small-molecule therapies can modulate the immune response to cancer by restoring the antitumor immunity, promoting more effective cytotoxic lymphocyte responses, and regulating tumor microenvironment, either directly or epigenetically. On the other hand, the combination of different mechanisms of small molecules with antibodies and other biologics demonstrated admirable synergistic effect in clinical settings for cancer treatment and may expand antibodies' usefulness for broader clinical applications. This chapter provides an overview of small-molecule immunotherapeutic approaches either as monotherapy or in combination for the treatment of cancer.
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Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Animales , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/inmunología , Humanos , Neoplasias/patología , Microambiente TumoralRESUMEN
We investigated the role of protein tyrosine phosphatase 1B (PTP1B) in mammary tumorigenesis using both genetic and pharmacological approaches. It has been previously shown that transgenic mice with a deletion mutation in the region of Erbb2 encoding its extracellular domain (referred to as NDL2 mice, for 'Neu deletion in extracellular domain 2') develop mammary tumors that progress to lung metastasis. However, deletion of PTP1B activity in the NDL2 transgenic mice either by breeding with Ptpn1-deficient mice or by treatment with a specific PTP1B inhibitor results in significant mammary tumor latency and resistance to lung metastasis. In contrast, specific overexpression of PTP1B in the mammary gland leads to spontaneous breast cancer development. The regulation of ErbB2-induced mammary tumorigenesis by PTB1B occurs through the attenuation of both the MAP kinase (MAPK) and Akt pathways. This report provides a rationale for the development of PTP1B as a new therapeutic target in breast cancer.
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Neoplasias Pulmonares/secundario , Neoplasias Mamarias Experimentales/enzimología , Proteínas Tirosina Fosfatasas/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Regulación hacia Abajo , Femenino , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/prevención & control , Sistema de Señalización de MAP Quinasas/fisiología , Glándulas Mamarias Animales/efectos de los fármacos , Neoplasias Mamarias Experimentales/etiología , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Datos de Secuencia Molecular , Fenotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor ErbB-3/metabolismo , Transducción de SeñalRESUMEN
A new olefination protocol for transition-metal-free cross-coupling of two carbene fragments arising from two different sources, namely, a nonfluorinated carbene fragment resulting from a diazo compound and a difluorocarbene fragment derived from Ruppert-Prakash reagent (TMSCF3) or TMSCF2Br, has been developed. This gem-difluoroolefination proceeds through the direct nucleophilic addition of diazo compounds to difluorocarbene followed by elimination of N2. Compared to previously reported Cu-catalyzed gem-difluoroolefination of diazo compounds with TMSCF3, which possesses a narrow substrate scope due to a demanding requirement on the reactivity of diazo compounds and in-situ-generated CuCF3, this transition-metal-free protocol affords a general and efficient approach to various disubstituted 1,1-difluoroalkenes, including difluoroacrylates, diaryldifluoroolefins, as well as arylalkyldifluoroolefins. In view of the ready availability of diazo compounds and difluorocarbene reagents and versatile transformations of 1,1-difluoroalkenes, this new gem-difluoroolefination method is expected to find wide applications in organic synthesis.
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Optimization of the ADME properties and pharmacokinetic (PK) profile of compounds is one of the critical activities in any medicinal chemistry campaign to discover a future clinical candidate. Finding ways to expedite the process to address ADME/PK shortcomings and reduce the number of compounds to synthesize is highly valuable. This article provides practical guidelines and a case study on the use of ML ADME models to guide compound design in small molecule lead optimization. These guidelines highlight that ML models cannot have an impact in a vacuum: they help advance a program when they have the trust of users, are tuned to the needs of the program, and are integrated into decision-making processes in a way that complements and augments the expertise of chemists.
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Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.
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Sistema de Señalización de MAP Quinasas , Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Animales , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Quinasas raf/metabolismo , Quinasas raf/antagonistas & inhibidores , Línea Celular Tumoral , Proteínas ras/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismoRESUMEN
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
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Descubrimiento de Drogas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Perros , Humanos , Ratones , Ratas , Administración Oral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Relación Estructura-ActividadRESUMEN
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
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The discovery and SAR of a series of potent renin inhibitors possessing a novel 3,4-diarylpiperidine scaffold are described herein. The resulting compound 38 exhibit low nanomolar plasma renin IC(50), had a clean CYP 3A4 profile and displayed micromolar affinity for the hERG channel. Furthermore, it was found to be efficacious in the double transgenic rat hypertension model and show good to moderate oral bioavailability in two animal species.
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Antihipertensivos/química , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Piperidinas/química , Piperidinas/uso terapéutico , Renina/antagonistas & inhibidores , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Disponibilidad Biológica , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Perros , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Piperidinas/farmacocinética , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The design and optimization of a novel isoxazole S(1) linker for renin inhibitor is described herein. This effort culminated in the identification of compound 18, an orally bioavailable, sub-nanomolar renin inhibitor even in the presence of human plasma. When compound 18 was found to inhibit CYP3A4 in a time dependent manner, two strategies were pursued that successfully delivered equipotent compounds with minimal TDI potential.
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Antihipertensivos/química , Diseño de Fármacos , Isoxazoles/química , Isoxazoles/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Dominio Catalítico , Activación Enzimática/efectos de los fármacos , Humanos , Isoxazoles/farmacología , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
3,3-Disubstituted oxetanes have been utilized as bioisosteres for gem-dimethyl and cyclobutane functionalities. We report the discovery of a novel class of oxetane indole-amine 2,3-dioxygenase (IDO1) inhibitors suitable for Q3W (once every 3 weeks) oral and parenteral dosing. A diamide class of IDO inhibitors was discovered through an automated ligand identification system (ALIS). Installation of an oxetane and fluorophenyl dramatically improved the potency. Identification of a biaryl moiety as an unconventional amide isostere addressed the metabolic liability of amide hydrolysis. Metabolism identification (Met-ID)-guided target design and the introduction of polarity resulted in the discovery of potent IDO inhibitors with excellent pharmacokinetic (PK) profiles in multiple species. To enable rapid synthesis of the key oxetane intermediate, a novel oxetane ring cyclization was also developed, as well as optimization of a literature route on kg scale. These IDO inhibitors may enable unambiguous proof-of-concept testing for the IDO1 inhibition mechanism for oncology.
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Inhibidores Enzimáticos , Éteres Cíclicos , Amidas , Ciclización , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismoRESUMEN
The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.
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Antihipertensivos/química , Piperidinas/química , Inhibidores de Proteasas/química , Renina/antagonistas & inhibidores , Compuestos de Espiro/química , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/uso terapéutico , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Perros , Diseño de Fármacos , Humanos , Hipertensión/tratamiento farmacológico , Macaca mulatta , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Ratas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
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Indoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Artritis/inducido químicamente , Artritis/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Indoles/farmacocinética , Indoles/uso terapéutico , Ligandos , Ratas , Subtipo EP2 de Receptores de Prostaglandina E/agonistas , Subtipo EP2 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP2 de Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
Our series of competitive antagonists against the G-protein coupled receptor P2Y(14) were found to be highly shifted in the presence of serum (>99% protein bound). A binding assay using 2% human serum albumin (HSA) was developed to guide further SAR studies and led to the identification of the zwitterion 2, which is substantially less shifted (18-fold) than our previous lead compound 1 (323-fold). However, as the bioavailability of 2 was low, a library of ester pro-drugs was prepared (7a-7j) and assessed in vitro. The most interesting candidates were then profiled in vivo and led to the identification of the pro-drug 7j, which possesses a substantially improved pharmacokinetic profile.
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Profármacos/química , Antagonistas del Receptor Purinérgico P2/química , Receptores Purinérgicos P2/química , Disponibilidad Biológica , Humanos , Microsomas Hepáticos/metabolismo , Profármacos/síntesis química , Profármacos/farmacocinética , Unión Proteica , Antagonistas del Receptor Purinérgico P2/síntesis química , Antagonistas del Receptor Purinérgico P2/farmacocinética , Receptores Purinérgicos P2/metabolismo , Relación Estructura-ActividadRESUMEN
An oral bioavailability issue encountered during the course of lead optimization in the renin program is described herein. The low F(po) of pyridone analogs was shown to be caused by a combination of poor passive permeability and gut efflux transport. Substitution of pyridone ring for a more lipophilic moiety (logD>1.7) had minimal effect on rMdr1a transport but led to increased passive permeability (P(app)>10 × 10(-6) cm/s), which contributed to overwhelm gut transporters and increase rat F(po). LogD and in vitro passive permeability determination were found to be key in guiding SAR and improve oral exposure of renin inhibitors.