RESUMEN
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While a half-life extended monoclonal antibody and 2 vaccines have recently been approved for infants and the elderly, respectively, options to prevent disease in immune-compromised patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, and long-acting PK when injected as an aqueous suspension, suggesting their potential to prevent complications following RSV infection over a period of 3 to 6 months with 1 or 2 long-acting intramuscular (IM) or subcutaneous (SC) injections in these immune-compromised patients.
Asunto(s)
Antivirales , Azetidinas , Oxindoles , Infecciones por Virus Sincitial Respiratorio , Compuestos de Espiro , Humanos , Infecciones por Virus Sincitial Respiratorio/prevención & control , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Animales , Oxindoles/química , Oxindoles/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/administración & dosificación , Antivirales/farmacología , Antivirales/química , Antivirales/administración & dosificación , Azetidinas/química , Azetidinas/farmacología , Azetidinas/administración & dosificación , Azetidinas/farmacocinética , Profilaxis Pre-Exposición/métodos , Inyecciones Intramusculares , Indoles/química , Indoles/administración & dosificación , Indoles/farmacología , Inyecciones Subcutáneas , Virus Sincitial Respiratorio Humano/efectos de los fármacos , Internalización del Virus/efectos de los fármacosRESUMEN
Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.
Asunto(s)
Lesión Pulmonar Aguda , Carbazoles , Diseño de Fármacos , Nucleotidiltransferasas , Pirrolidinas , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Ratones , Masculino , Humanos , Ratas , Carbazoles/síntesis química , Carbazoles/farmacología , Carbazoles/química , Carbazoles/uso terapéutico , Carbazoles/farmacocinética , Pirrolidinas/farmacología , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/uso terapéutico , Pirrolidinas/farmacocinética , Nucleotidiltransferasas/antagonistas & inhibidores , Nucleotidiltransferasas/metabolismo , Lipopolisacáridos , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Compuestos de Espiro/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/química , Relación Estructura-Actividad , Simulación del Acoplamiento MolecularRESUMEN
Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.
Asunto(s)
Inductores del Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Transportador 1 de Anión Orgánico Específico del Hígado , Rifampin , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/antagonistas & inhibidores , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Masculino , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/antagonistas & inhibidores , Miembro 1B3 de la Familia de los Transportadores de Solutos de Aniones Orgánicos/metabolismo , Adulto , Inhibidores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Rifampin/farmacología , Rifampin/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacología , Femenino , Adulto Joven , Administración Oral , Persona de Mediana Edad , Voluntarios Sanos , Área Bajo la Curva , Itraconazol/farmacología , Itraconazol/administración & dosificación , Itraconazol/farmacocinética , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacologíaRESUMEN
BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.
Asunto(s)
Arritmias Cardíacas , Canal de Potasio ERG1/antagonistas & inhibidores , Compuestos de Espiro/farmacocinética , Tiofenos/farmacocinética , Analgésicos Opioides/farmacocinética , Animales , Arritmias Cardíacas/etiología , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatología , Arritmias Cardíacas/prevención & control , Línea Celular , Cricetulus , Humanos , Concentración 50 Inhibidora , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/metabolismo , Síndrome de QT Prolongado/fisiopatología , Moduladores del Transporte de Membrana/farmacología , Quinidina/farmacocinética , Distribución Tisular , Bloqueadores del Canal de Sodio Activado por Voltaje/farmacocinéticaRESUMEN
Atogepant is a selective, oral calcitonin gene-related peptide receptor antagonist in development for preventive treatment of migraine. This randomized, double-blind, phase 1 crossover study evaluated the cardiac repolarization effect of a single supratherapeutic (300 mg) atogepant dose vs placebo in healthy adults. Moxifloxacin 400 mg was the open-label active control. The primary end point was a change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Sixty participants were randomized to atogepant 300 mg, placebo, and moxifloxacin; 59 (98.3%) completed all interventions. Assay sensitivity was confirmed: lower 90% confidence interval limit for QTcF interval change from baseline (ΔΔQTcF) for moxifloxacin was >5 millisecond vs placebo at prespecified 2-, 3-, and 4-hour time points. Following single-dose atogepant 300 mg, mean atogepant ΔΔQTcF and upper 90% confidence interval limits were lower than the 10-millisecond threshold at all time points. Atogepant mean peak plasma concentration was 3197 ng/mL, area under the concentration-time curve from time 0 to time t was 16 640 ng ⢠h/mL, area under the concentration-time curve from time 0 to 24 hours was 16 607 ng ⢠h/mL, and median time to peak plasma concentration was 2.1 hours. The incidence of adverse events was low; no serious adverse events or elevations of liver enzymes were reported. Overall, a single supratherapeutic dose of atogepant was safe and did not impact cardiac repolarization in healthy participants.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Moxifloxacino/efectos adversos , Piperidinas/efectos adversos , Piridinas/efectos adversos , Pirroles/efectos adversos , Compuestos de Espiro/efectos adversos , Adolescente , Adulto , Área Bajo la Curva , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/administración & dosificación , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Estudios Cruzados , Método Doble Ciego , Electrocardiografía , Femenino , Humanos , Masculino , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Pirroles/administración & dosificación , Pirroles/farmacocinética , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacocinética , Adulto JovenRESUMEN
Atogepant is a selective oral calcitonin gene-related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single-dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open-label, parallel-group, single-dose phase 1 trial. Thirty-two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, â¼2 hours) with an apparent terminal elimination half-life of â¼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were -4%, -12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/farmacocinética , Hepatopatías/fisiopatología , Piperidinas/farmacocinética , Piridinas/farmacocinética , Pirroles/farmacocinética , Compuestos de Espiro/farmacocinética , Administración Oral , Anciano , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina/efectos adversos , Femenino , Semivida , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Piridinas/efectos adversos , Pirroles/efectos adversos , Índice de Severidad de la Enfermedad , Compuestos de Espiro/efectos adversosRESUMEN
Persistent androgen receptor (AR) activation drives therapeutic resistance to second-generation AR pathway inhibitors and contributes to the progression of advanced prostate cancer. One resistance mechanism is point mutations in the ligand binding domain of AR that can transform antagonists into agonists. The AR F877L mutation, identified in patients treated with enzalutamide or apalutamide, confers resistance to both enzalutamide and apalutamide. Compound 4 (JNJ-pan-AR) was identified as a pan-AR antagonist with potent activity against wild-type and clinically relevant AR mutations including F877L. Metabolite identification studies revealed a latent bioactivation pathway associated with 4. Subsequent lead optimization of 4 led to amelioration of this pathway and nomination of 5 (JNJ-63576253) as a clinical stage, next-generation AR antagonist for the treatment of castration-resistant prostate cancer (CRPC).
Asunto(s)
Antagonistas de Receptores Androgénicos/farmacología , Nitrilos/farmacología , Picolinas/farmacología , Piperidinas/farmacología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Piridinas/farmacología , Compuestos de Espiro/farmacología , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/uso terapéutico , Animales , Biotransformación , Línea Celular Tumoral , Perros , Descubrimiento de Drogas , Resistencia a Antineoplásicos/genética , Hepatocitos/metabolismo , Humanos , Masculino , Modelos Moleculares , Mutación , Nitrilos/farmacocinética , Nitrilos/uso terapéutico , Picolinas/farmacocinética , Picolinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
Transient receptor potential vanilloid 4 (TRPV4) channels expressed on pulmonary endothelial cells are activated by elevated pulmonary vascular pressure, resulting in endothelial shape change, pulmonary barrier disruption, and edema. As such, TRPV4 blocker GSK2798745 was recently investigated in phase I/IIa trials to reduce pulmonary edema caused by heart failure (HF). In the absence of a suitable TRPV4 target engagement biomarker, we hypothesized that an ex vivo assay could be used to predict pharmacological activity at the intended site of action (endothelial cells) of subjects. In this assay, the ability of GSK2798745 to block TRPV4 agonist GSK1016790-induced impendence reduction in human umbilical vein endothelial cells (HUVECs) in the presence of human whole blood was assessed. Blood from healthy volunteers drawn 1-12 hours after single or repeated dose of GSK2798745 (5 mg) inhibited GSK1016790-induced impedance reduction by ≥85%. Similarly, blood samples from 16 subjects with HF dosed with GSK2798745 (2.4 mg) inhibited GSK1016790-induced HUVEC impedance reduction by ≥58% 1-24 hours after single dosing and ≥78% 1-24 hours after 7 days of repeated dosing. No inhibition was detected using blood from placebo subjects. Using matched GSK2798745 plasma levels, a pharmacokinetic/pharmacodynamic (PK/PD) relationship was calculated as 2.9 nM IC50, consistent with the 6.5 nM IC50 of GSK2798745 obtained from a rat in vivo PK/PD model of pulmonary edema after correcting for rat-to-human differences. These results indicate that circulating levels of GSK2798745 in the recently completed phase I/IIa trials were sufficient to block TRPV4 in lung vascular endothelial cells to a large extent, supporting this dosing regimen for assessing efficacy in HF. SIGNIFICANCE STATEMENT: In the absence of a suitable target engagement biomarker, we developed an ex vivo assay to predict the pharmacological activity of the transient receptor potential vanilloid 4 (TRPV4) blocker GSK2798745 in healthy volunteers and subjects with heart failure (HF) from phase I/IIa trials. The potency values from the ex vivo assay were consistent with those predicted from a rat in vivo pharmacokinetic/pharmacodynamic model of pulmonary edema, strongly suggesting that circulating levels of GSK2798745 were sufficient to robustly block TRPV4, supporting use of GSK2798745 for assessing efficacy in HF.
Asunto(s)
Bencimidazoles/sangre , Bencimidazoles/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Compuestos de Espiro/sangre , Compuestos de Espiro/farmacología , Canales Catiónicos TRPV/metabolismo , Animales , Bencimidazoles/farmacocinética , Impedancia Eléctrica , Células Endoteliales de la Vena Umbilical Humana/citología , Humanos , Masculino , Terapia Molecular Dirigida , Ratas , Compuestos de Espiro/farmacocinética , Canales Catiónicos TRPV/antagonistas & inhibidoresRESUMEN
Atogepant is a potent, selective, oral calcitonin gene-related peptide (CGRP) receptor antagonist in development for migraine prevention. The chemical structure of atogepant is distinct from previous CGRP receptor antagonists, which were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report the safety, tolerability, and pharmacokinetics (PKs) of a once-daily supratherapeutic dose (170 mg) of atogepant for 28 days from a randomized, double-blind, placebo-controlled phase I trial in healthy participants. Overall safety, hepatic safety, and plasma PK parameters were evaluated. Thirty-four participants aged 23-55 years enrolled; 28 (82.4%) completed the study in accordance with the protocol. Multiple doses of 170 mg atogepant for 28 consecutive days were generally well-tolerated. All adverse events (AEs; reported in 87.0% of the atogepant group; 72.7%, placebo) were mild in severity except one serious AE of subarachnoid hemorrhage due to a bicycle accident and not considered related to treatment. There were two discontinuations due to AEs, both with atogepant, one considered possibly related to treatment. Over 28 days of treatment, no participant receiving atogepant had an ALT elevation above 1.5 × upper limit of normal. Change from baseline in serum ALT levels was not different between atogepant and placebo. Atogepant is rapidly absorbed (median time to maximum plasma concentration, ~ 2 hours) with an apparent terminal half-life of ~ 11 hours, and no evidence of accumulation after once-daily dosing. Overall, atogepant at a high oral dose is safe and well-tolerated in healthy participants with no clinically meaningful elevations in ALT.
Asunto(s)
Alanina Transaminasa/sangre , Hígado/efectos de los fármacos , Piperidinas/efectos adversos , Piridinas/efectos adversos , Pirroles/efectos adversos , Compuestos de Espiro/efectos adversos , Administración Oral , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Hígado/enzimología , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Trastornos Migrañosos/prevención & control , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Placebos/administración & dosificación , Placebos/efectos adversos , Piridinas/administración & dosificación , Piridinas/farmacocinética , Pirroles/administración & dosificación , Pirroles/farmacocinética , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/farmacocinética , Adulto JovenRESUMEN
Oliceridine (Olinvyk™, Trevena, Inc.) is a novel µ opioid agonist that was recently approved in the USA for use in adults for the management of acute pain severe enough to require an intravenous opioid analgesic and for whom alternative treatments are inadequate. Unlike opioid agonists currently in use, the interaction of oliceridine with the opioid receptor is selective to the G protein pathway, with low potency for ß-arrestin recruitment, which may lead to fewer opioid-related adverse events. This article summarizes the milestones in the development of oliceridine leading to this first approval.
Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/administración & dosificación , Aprobación de Drogas , Compuestos de Espiro/administración & dosificación , Tiofenos/administración & dosificación , Dolor Agudo/diagnóstico , Administración Intravenosa , Adulto , Analgesia Controlada por el Paciente/efectos adversos , Analgesia Controlada por el Paciente/métodos , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacocinética , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Relación Dosis-Respuesta a Droga , Humanos , Dimensión del Dolor , Receptores Opioides mu/agonistas , Índice de Severidad de la Enfermedad , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/farmacocinética , Tiofenos/efectos adversos , Tiofenos/farmacocinéticaRESUMEN
Tellurium compounds have been described as potential leishmanicides, bearing promising leishmanicidal and antimalarial effects. Therefore, the present study investigated the pharmacological potential of the organotellurane compound RF07 through preADMET parameters, such as absorption, distribution, metabolism and excretion. After studying the pharmacokinetic properties of RF07, studies were carried out on dogs naturally infected with visceral leishmaniasis after the administration of RF07, in order to assess pathophysiological parameters. Thus, dogs were divided into 4 groups with administration of daily intraperitoneal injections for 3 weeks (containing RF07 or placebo). During the trial, hematological parameters, renal and hepatic toxicity were evaluated. Serum urea, creatinine, alkaline phosphatase, transaminases (GOT and GPT), as well as hemogram results, were evaluated before the first administration and during the second and third weeks after the start of the treatment. In dogs with VL, RF07 improved liver damage, regulated GPT levels and significantly decreased leukocyte count, promoting its regularization. These phenomena occurred at the end of the third week of treatment. The administration of RF07 promoted a significant decrease in the average levels of GOT and GPT after the third week of treatment and did not significantly alter the hematological parameters. The application of RF07 in the treatment of visceral leishmaniasis suggests that it is an alternative to the disease, since the reversal of clinical signs in dogs with VL requires the use of 0.6â¯mg/kg.
Asunto(s)
Antiprotozoarios , Leishmaniasis Visceral , Compuestos Organometálicos , Compuestos de Espiro , Telurio , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Animales , Antiprotozoarios/farmacocinética , Antiprotozoarios/farmacología , Antiprotozoarios/uso terapéutico , Aspartato Aminotransferasas/sangre , Recuento de Células Sanguíneas , Peso Corporal/efectos de los fármacos , Creatinina/sangre , Perros , Absorción Intestinal , Riñón/efectos de los fármacos , Riñón/patología , Leishmaniasis Visceral/sangre , Leishmaniasis Visceral/tratamiento farmacológico , Leishmaniasis Visceral/patología , Leishmaniasis Visceral/veterinaria , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Modelos Biológicos , Compuestos Organometálicos/farmacocinética , Compuestos Organometálicos/farmacología , Compuestos Organometálicos/uso terapéutico , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Compuestos de Espiro/uso terapéutico , Telurio/farmacocinética , Telurio/farmacología , Telurio/uso terapéutico , Urea/sangreRESUMEN
We report the design, synthesis, and evaluation of a series of 1-oxa-8-azaspiro[4.5]decane and 1,5-dioxa-9-azaspiro[5.5]undecane derivatives as selective σ1 receptor ligands. All seven ligands exhibited nanomolar affinity for σ1 receptors (Ki(σ1) = 0.47 - 12.1 nM) and moderate selectivity over σ2 receptors (Ki(σ2)/ Ki(σ1) = 2 - 44). Compound 8, with the best selectivity among these ligands, was selected for radiolabeling and further evaluation. Radioligand [18F]8 was prepared via nucleophilic 18F-substitution of the corresponding tosylate precursor, with an overall isolated radiochemical yield of 12-35%, a radiochemical purity of greater than 99%, and molar activity of 94 - 121 GBq/µmol. Biodistribution studies of [18F]8 in mice demonstrated high initial brain uptake at 2 min. Pretreatment with SA4503 resulted in significantly reduced brain-to-blood ratio (70% - 75% at 30 min). Ex vivo autoradiography in ICR mice demonstrated high accumulation of the radiotracer in σ1 receptor-rich brain areas. These findings suggest that [18F]8 could be a lead compound for further structural modifications to develop potential brain imaging agents for σ1 receptors.
Asunto(s)
Compuestos Aza/farmacocinética , Receptores sigma/análisis , Compuestos de Espiro/farmacocinética , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Encéfalo/diagnóstico por imagen , Relación Dosis-Respuesta a Droga , Radioisótopos de Flúor/química , Ligandos , Masculino , Ratones , Ratones Endogámicos ICR , Estructura Molecular , Ensayo de Unión Radioligante , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-Actividad , Distribución Tisular , Receptor Sigma-1RESUMEN
Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of ß-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure-activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of ß-hemoglobinopathies, including SCD.
Asunto(s)
Azetidinas/farmacología , Células Precursoras Eritroides/efectos de los fármacos , Hemoglobina Fetal/metabolismo , Compuestos de Espiro/farmacología , Animales , Azetidinas/síntesis química , Azetidinas/farmacocinética , Diseño de Fármacos , Estabilidad de Medicamentos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Macaca fascicularis , Microsomas Hepáticos/metabolismo , Estructura Molecular , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
Ranirestat is an aldose reductase inhibitor hypothesized to improve diabetic neuropathy. An open-label, single-dose, parallel-group study was conducted to compare pharmacokinetic (PK) characteristics of an oral dose of ranirestat across subjects with normal hepatic function and patients with mild and moderate hepatic impairment because ranirestat is expected to be used by patients with diabetes mellitus, possibly including those with hepatic impairment. To evaluate the necessity for dose adjustment, PK profiles and tolerability were studied at the dose of 40 mg, the expected optimal clinical dose in patients with diabetic neuropathy and normal hepatic function. In total, 20 subjects, including 5, 10, and 5 subjects with normal hepatic function, mild hepatic impairment, and moderate hepatic impairment, respectively, completed the study. Serial PK sampling was conducted up to 504 hours, and PK parameters were calculated and compared between healthy subjects and patients with mild or moderate hepatic impairment. The geometric mean ratios of peak concentration and area under the concentration-time curve in patients with mild hepatic impairment (90%CI) were 86.7% (55.3% to 135.9%) and 84.7% (68.5% to 104.8%), respectively. The values in patients with moderate hepatic impairment were 81.3% (48.8% to 135.5%) and 91.7% (72.1% to 116.7%), respectively. These results demonstrated that plasma ranirestat exposure and the plasma protein binding of the drug were not substantially altered by normal, mild, or moderate hepatic impairment (protein binding 99.22%, 99.29%, and 99.00%, respectively). All adverse events were mild in severity. Based on these findings, no dose adjustment will be required for ranirestat in patients with mild or moderate hepatic impairment.
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Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Hepatopatías/metabolismo , Pirazinas/efectos adversos , Pirazinas/farmacocinética , Compuestos de Espiro/efectos adversos , Compuestos de Espiro/farmacocinética , Adulto , Anciano , Área Bajo la Curva , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/sangre , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Unión Proteica , Pirazinas/administración & dosificación , Pirazinas/sangre , Compuestos de Espiro/administración & dosificación , Compuestos de Espiro/sangreRESUMEN
A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.
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Fármacos Anti-VIH/farmacología , VIH-1/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Cetonas/farmacología , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacocinética , Línea Celular Tumoral , Perros , Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacocinética , Humanos , Cetonas/síntesis química , Cetonas/farmacocinética , Pruebas de Sensibilidad Microbiana , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacologíaRESUMEN
Semisynthetic artemisinins and other bioactive peroxides are best known for their powerful antimalarial activities, and they also show substantial activity against schistosomes-another hemoglobin-degrading pathogen. Building on this discovery, we now describe the initial structure-activity relationship (SAR) of antischistosomal ozonide carboxylic acids OZ418 (2) and OZ165 (3). Irrespective of lipophilicity, these ozonide weak acids have relatively low aqueous solubilities and high protein binding values. Ozonides with para-substituted carboxymethoxy and N-benzylglycine substituents had high antischistosomal efficacies. It was possible to increase solubility, decrease protein binding, and maintain the high antischistosomal activity in mice infected with juvenile and adult Schistosoma mansoni by incorporating a weak base functional group in these compounds. In some cases, adding polar functional groups and heteroatoms to the spiroadamantane substructure increased the solubility and metabolic stability, but in all cases decreased the antischistosomal activity.
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Adamantano/uso terapéutico , Ácidos Carboxílicos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Esquistosomicidas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Adamantano/análogos & derivados , Adamantano/farmacocinética , Adamantano/toxicidad , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/toxicidad , Línea Celular Tumoral , Femenino , Células HEK293 , Compuestos Heterocíclicos con 1 Anillo/síntesis química , Compuestos Heterocíclicos con 1 Anillo/farmacocinética , Compuestos Heterocíclicos con 1 Anillo/toxicidad , Humanos , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Schistosoma mansoni/efectos de los fármacos , Esquistosomiasis mansoni/tratamiento farmacológico , Esquistosomicidas/síntesis química , Esquistosomicidas/farmacocinética , Esquistosomicidas/toxicidad , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/toxicidad , Relación Estructura-ActividadRESUMEN
The dissipation dynamic and residues of spiroxamine in open-field-grown strawberries were determined using liquid chromatography tandem mass spectrometry (LC-MS/MS). Spiroxamine application was performed according to Egyptian good agricultural practices recommendation. A QuEChERS-based extraction method along with direct analysis with an LC-MS/MS analytical method were optimized and validated, and the specificity of the techniques used was considered satisfactory. Good linearity (R2 > 0.999) was obtained for spiroxamine within the range of 0.001-0.1 µg/ml. The mean recoveries varied between 97.1 and 108.2%, with inter- and intra-day precision (RSD) <4.9%. The limit of quantitation for spiroxamine was 0.001 mg/kg. The results indicated that spiroxamine degradation in strawberry followed first-order kinetics (R2 > 0.9929) with an estimated half-life value of 4.71 days. Considering the Australian maximum residue limit (0.05 mg/kg) in strawberry and based on the results from residue trials with a preharvest interval of 14 days for strawberry, compliance can be expected. The present results could provide guidance to fully evaluate the risks of spiroxamine residues, preventing any potential health risk to consumers.
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Cromatografía Liquida/métodos , Fragaria , Fungicidas Industriales/análisis , Residuos de Plaguicidas/análisis , Compuestos de Espiro/análisis , Egipto , Inocuidad de los Alimentos , Fragaria/química , Fragaria/metabolismo , Fungicidas Industriales/farmacocinética , Modelos Lineales , Residuos de Plaguicidas/farmacocinética , Reproducibilidad de los Resultados , Medición de Riesgo , Sensibilidad y Especificidad , Compuestos de Espiro/farmacocinética , Espectrometría de Masas en Tándem/métodosRESUMEN
We report the discovery of a novel indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor class through the affinity selection of a previously unreported indole-based DNA-encoded library (DEL). The DEL exemplar, spiro-chromane 1, had moderate IDO1 potency but high in vivo clearance. Series optimization quickly afforded a potent, low in vivo clearance lead 11. Although amorphous 11 was highly bio-available, crystalline 11 was poorly soluble and suffered disappointingly low bio-availability because of solubility-limited absorption. A prodrug approach was deployed and proved effective in discovering the highly bio-available phosphonooxymethyl 31, which rapidly converted to 11 in vivo. Obtaining crystalline 31 proved problematic, however; thus salt screening was performed in an attempt to circumvent this obstacle and successfully delivered greatly soluble and bio-available crystalline tris-salt 32. IDO1 inhibitor 32 is characterized by a low calculated human dose, best-in-class potential, and an unusual inhibition mode by binding the IDO1 heme-free (apo) form.
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ADN/química , Inhibidores Enzimáticos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores , Profármacos/farmacología , Compuestos de Espiro/farmacología , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Euterios , Masculino , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacocinética , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
p300 and CREB-binding protein (CBP) are ubiquitously expressed pleiotropic lysine acetyltransferases and play a key role as transcriptional co-activators that are essential for a multitude of cellular processes. Despite great importance, there is a lack of highly selective, potent, druglike p300/CBP inhibitors. Through the artificial-intelligence-assisted drug discovery pipeline and further optimization, we reported the discovery of novel, highly selective, potent small-molecule inhibitors of p300/CBP histone acetyltransferases (HAT) with desired druglike properties, exemplified by B026. Our data demonstrated that B026, with half maximal inhibitory concentration (IC50) values of 1.8 nM to p300 and 9.5 nM to CBP enzyme inhibitory activity, is the most potent, selective p300/CBP HAT inhibitor. Moreover, B026 achieves significant and dose-dependent tumor growth inhibition in an animal model of human cancer, suggesting that B026 is a highly promising p300/CBP HAT inhibitor and warrants extensive preclinical investigation as a potential clinical development candidate.
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Antineoplásicos/uso terapéutico , Proteína de Unión a CREB/antagonistas & inhibidores , Proteína p300 Asociada a E1A/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Neoplasias/tratamiento farmacológico , Compuestos de Espiro/uso terapéutico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Conjuntos de Datos como Asunto , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Redes Neurales de la Computación , Ratas Sprague-Dawley , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Relación Estructura-ActividadRESUMEN
BACKGROUND: Anisatin is a neurotoxic sesquiterpene dilactone wildly found in plants of the family Illiciaceae. Due to morphological similarities among Illiciaceae fruits, fatal poisonings are frequent. OBJECTIVE: This study is aimed at developing a rapid, simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determine anisatin's bioavailability in mouse blood and the method's application to pharmacokinetics. METHODS: Blood samples were preprocessed by protein precipitation using acetonitrile. Salicin (internal standard, IS) and anisatin were gradient-eluted by a mobile phase of methanol and water (0.1% formic acid) in a UPLC BEH C18 column. This step involved using an electrospray ionization source of anisatin at a mass-to-charge ratio (m/z) of 327.1 â 127.0 and IS at m/z 285.1 â 122.9 in the negative ion mode with multiple reaction monitoring. RESULTS: The calibration curve ranged from 1 to 2000 ng/ml (r > 0.995), with the method's accuracy ranging from 86.3% to 106.9%. Intraday and interday precision were lower than 14%, and the matrix effect was between 93.9% and 103.3%. The recovery rate was higher than 67.2%. CONCLUSIONS: The developed UPLC-MS/MS method was successfully used for a pharmacokinetic study of oral (1 mg/kg) and intravenous (0.5 mg/kg) administration of anisatin to mice-the absolute bioavailability of anisatin in the mouse blood was 22.6%.