RESUMEN
Ozanimod is approved for the treatment of relapsing forms of multiple sclerosis. Absorption, metabolism, and excretion of ozanimod were investigated after a single oral dose of 1.0 mg [14C]ozanimod hydrochloride to six healthy subjects. In vitro experiments were conducted to understand the metabolic pathways and enzymes involved in the metabolism of ozanimod and its active metabolites. The total mean recovery of the administered radioactivity was â¼63%, with â¼26% and â¼37% recovered from urine and feces, respectively. Based on exposure, the major circulating components were active metabolite CC112273 and inactive metabolite RP101124, which together accounted for 50% of the circulating total radioactivity exposure, whereas ozanimod accounted for 6.7% of the total radioactive exposure. Ozanimod was extensively metabolized, with 14 metabolites identified, including two major active metabolites (CC112273 and CC1084037) and one major inactive metabolite (RP101124) in circulation. Ozanimod is metabolized by three primary pathways, including aldehyde dehydrogenase and alcohol dehydrogenase, cytochrome P450 isoforms 3A4 and 1A1, and reductive metabolism by gut microflora. The primary metabolite RP101075 is further metabolized to form major active metabolite CC112273 by monoamine oxidase B, which further undergoes reduction by carbonyl reductases to form CC1084037 or CYP2C8-mediated oxidation to form RP101509. CC1084037 is oxidized rapidly to form CC112273 by aldo-keto reductase 1C1/1C2 and/or 3ß- and 11ß-hydroxysteroid dehydrogenase, and this reversible oxidoreduction between two active metabolites favors CC112273. The ozanimod example illustrates the need for conducting timely radiolabeled human absorption, distribution, metabolism, and excretion studies for characterization of disproportionate metabolites and assessment of exposure coverage during drug development. SIGNIFICANCE STATEMENT: Absorption, metabolism, and excretion of ozanimod were characterized in humans, and the enzymes involved in complex metabolism were elucidated. Disproportionate metabolites were identified, and the activity of these metabolites was determined.
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Indanos/administración & dosificación , Indanos/metabolismo , Oxadiazoles/administración & dosificación , Oxadiazoles/metabolismo , Moduladores de los Receptores de fosfatos y esfingosina 1/administración & dosificación , Moduladores de los Receptores de fosfatos y esfingosina 1/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismo , Administración Oral , Adulto , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.
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Regulación de la Expresión Génica , Péptido Hidrolasas/química , Teratógenos/química , Talidomida/química , Factores de Transcripción/química , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Homocigoto , Humanos , Inmunohistoquímica , Células Madre Pluripotentes Inducidas , Ligandos , Masculino , Ratones , Ratones Transgénicos , Mutación , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Péptido Hidrolasas/genética , Proteolisis , Conejos , Testículo/metabolismo , Factores de Transcripción/genética , Ubiquitina-Proteína Ligasas/metabolismo , Dedos de ZincRESUMEN
1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [(14)C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL). 2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1-2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5-32% of dose) was recovered in urine/feces across all species, the highest in human feces. 3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4-46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively. 4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways.
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Ciclohexanoles/metabolismo , Ciclohexanoles/farmacocinética , Proteínas Quinasas JNK Activadas por Mitógenos/administración & dosificación , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacocinética , Purinas/metabolismo , Purinas/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Bilis/química , Biotransformación , Radioisótopos de Carbono , Cromatografía Líquida de Alta Presión , Ciclohexanoles/administración & dosificación , Ciclohexanoles/química , Perros , Relación Dosis-Respuesta a Droga , Heces/química , Femenino , Humanos , Masculino , Espectrometría de Masas , Metaboloma , Metabolómica , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Purinas/administración & dosificación , Purinas/química , Ratas Sprague-DawleyRESUMEN
1. In vitro metabolism of Tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, selective c-Jun amino-terminal kinase (JNK) inhibitor, was investigated in mouse, rat, rabbit, dog, monkey and human hepatocytes over 4 h. The extent of metabolism of [(14)C]tanzisertib was variable, with <10% metabolized in dog and human, <20% metabolized in rabbit and monkey and >75% metabolized in rat and mouse. Primary metabolic pathways in human and dog hepatocytes, were direct glucuronidation and oxidation of cyclohexanol to a keto metabolite, which was subsequently reduced to parent or cis-isomer, followed by glucuronidation. Rat and mouse produced oxidative metabolites and cis-isomer, including direct glucuronides and sulfates of tanzisertib and cis-isomer. 2. Enzymology of oxido-reductive pathways revealed that human aldo-keto reductases AKR1C1, 1C2, 1C3 and 1C4 were responsible for oxido-reduction of tanzisertib, CC-418424 and keto tanzisertib. Characterizations of enzyme kinetics revealed that AKR1C4 had a high affinity for reduction of keto tanzisertib to tanzisertib compared to other isoforms. These results demonstrate unique stereoselectivity of the reductive properties documented by human AKR1C enzymes for the same substrate. 3. Characterization of UGT isoenzymes in glucuronidation of tanzisertib and CC-418424 revealed that, tanzisertib glucuronide was catalyzed by: UGT1A1, 1A4, 1A10 and 2B4, while CC-418424 glucuronidation was catalyzed by UGT2B4 and 2B7.
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Aldehído Reductasa/metabolismo , Glucuronosiltransferasa/metabolismo , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Microsomas Hepáticos/enzimología , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/farmacocinética , Aldo-Ceto Reductasas , Animales , Perros , Femenino , Humanos , MAP Quinasa Quinasa 4/metabolismo , Macaca fascicularis , Masculino , Ratones , Conejos , Ratas , Ratas Sprague-DawleyRESUMEN
Pomalidomide, a potent novel immunomodulatory agent, has been developed as a racemic mixture of its R- and S-isomers. Pharmacokinetic (PK) analyses were conducted to determine the PK disposition of the isomers from their PK profiles in humans and monkeys. Modeling and simulation were performed to describe the observed PK profiles and explore potential differences in isomer disposition and exposure. PK profiles of S- and R-isomers were measured in a human absorption, distribution, metabolism, and excretion study after oral administration of racemate. PK profiles of S- and R-isomers were measured in monkeys after intravenous and oral administration of S- or R-isomers and pomalidomide racemate. Modeling and simulation were performed using NONMEM 7.2 (Globomax, Ellicott City, MD) to describe the observed PK profiles of S- and R-isomers in humans and monkeys. The results showed that in humans, the in vivo elimination rate of pomalidomide isomers was lower than the R-/S-interconversion rate, resulting in no clinically relevant difference in overall exposure to the two isomers. However, in monkeys, the in vivo elimination rate was higher than the R-/S-interconversion rate, resulting in 1.72- and 1.55-fold differences in R- versus S-isomer exposures. Monte Carlo simulation indicated that exposure to R- and S-enantiomers in humans should be comparable even if single isomers are administered. Thus, in humans, rapid isomeric interconversion of pomalidomide isomers results in comparable exposure to R- and S-enantiomers regardless of whether pomalidomide is administered as a single enantiomer or as a racemate, therefore justifying the clinical development of pomalidomide as a racemate.
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Talidomida/análogos & derivados , Animales , Humanos , Macaca fascicularis , Masculino , Modelos Biológicos , Método de Montecarlo , Estereoisomerismo , Talidomida/química , Talidomida/farmacocinéticaRESUMEN
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
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Acetamidas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Piperazinas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Lenalidomide is an immunomodulatory drug and is very effective in the management of a number of malignancies, including multiple myeloma. Like thalidomide, lenalidomide interacts with the cereblon E3 ligase complex, which results in targeted destruction of proteins. This study was conducted to study the teratogenic potential of lenalidomide when administered to pregnant cynomolgus monkeys. Lenalidomide was administered orally on gestation days 20-50 at dosages of 0 (vehicle control), 0.5, 1, 2 and 4 mg/kg/day. Thalidomide was used as a positive control and was administered orally at 15 mg/kg/day on gestation days 26-28. Each group consisted of 5 pregnant monkeys. Pregnancy was terminated on gestation day 100 ± 1 by cesarean section and fetuses examined for external, internal and skeletal changes. Intrauterine loss was 40% in the thalidomide group and 20 % in each of the lenalidomide 2 and 4 mg/kg/day groups. Treatment with lenalidomide and thalidomide resulted in no effects on placental weights, fetal body weights and body measurements. External fetal examination revealed malformations in fetuses of all lenalidomide-treated groups, including malformations of upper and lower extremities. These external malformations had correlated skeletal findings and were similar to those seen in the thalidomide-treated group, where two of three fetuses showed the classic thalidomide syndrome of malformed upper and lower extremities. A no-observed-adverse-effect level was not identified in this study, and the mean maternal exposures at the lowest dosage, where fetal malformations were observed, were 5-folder lower than the exposures observed in the MM patients treated with 25 mg of lenalidomide.
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Cesárea , Talidomida , Animales , Femenino , Embarazo , Lenalidomida/toxicidad , Talidomida/toxicidad , Macaca fascicularis , Placenta , Administración OralRESUMEN
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Asunto(s)
Acetamidas/uso terapéutico , Antagonistas del Receptor de Bradiquinina B1 , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piperazinas/uso terapéutico , Acetamidas/síntesis química , Acetamidas/química , Animales , Perros , Concentración 50 Inhibidora , Ratones , Modelos Animales , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Conejos , Ratas , Receptor de Bradiquinina B1/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 µCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and <7% of the excreted radioactivity. The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity and 34% of excreted radioactivity. The only other radioactive components that represented >4% of the excreted radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent.
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Inhibidores de Fosfodiesterasa 4/administración & dosificación , Inhibidores de Fosfodiesterasa 4/farmacocinética , Talidomida/análogos & derivados , Administración Oral , Adulto , Radioisótopos de Carbono , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/metabolismo , Radiactividad , Talidomida/administración & dosificación , Talidomida/química , Talidomida/metabolismo , Talidomida/farmacocinética , Factores de Tiempo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
Asunto(s)
Bencilaminas/química , Antagonistas del Receptor de Bradiquinina B1 , Sulfonamidas/química , Tetrahidronaftalenos/química , Administración Oral , Animales , Dolor/tratamiento farmacológico , Ratas , Receptor de Bradiquinina B1/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
Motesanib diphosphate is a novel, investigational, highly selective oral inhibitor of the receptor tyrosine kinases vascular endothelial growth factor receptors 1, 2, and 3, the platelet-derived growth factor receptor, and the stem cell factor receptor (Kit). The in vitro metabolic profiles of [(14)C]motesanib were examined by using microsomes and hepatocytes from preclinical species and humans. Several oxidative metabolites were observed and characterized by tandem mass spectrometry, nuclear magnetic resonance spectroscopy, and coinjection with authentic standards. Cytochrome P450 (P450) 3A4 is the major isozyme involved in the oxidative biotransformation of motesanib, but the CYP2D6 and CYP1A isozymes also make minor contributions. In hepatocyte incubations, oxidative and conjugative pathways were observed for all species examined, and indoline N-glucuronidation was the dominant pathway. Three less common and novel phase II conjugates of the indoline nitrogen were detected in hepatocytes and in microsomes supplemented with specific cofactors, including N-carbamoyl glucuronide, N-glucose, and N-linked beta-N-acetylglucosamine. An N-glucuronide metabolite was the most frequently observed phase II conjugate in liver microsomes of all species, whereas the N-acetylglucosamine conjugate was observed only in monkey liver microsomes. Incubations with recombinant human UDP-glucuronosyltransferases (UGTs) and inhibition by the UGT1A4 and UGT1A1 substrates/inhibitors imipramine and bilirubin suggested that UGT1A4 is the major UGT isozyme catalyzing the N-glucuronidation of motesanib, with a minor contribution from UGT1A1. The in vitro metabolic profiles were similar between the human and preclinical species examined. All metabolites found in humans were also detected in other species.
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Glucurónidos , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/metabolismo , Administración Oral , Biotransformación , Sistema Enzimático del Citocromo P-450 , Glucurónidos/metabolismo , Hepatocitos/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Indoles/metabolismo , Espectroscopía de Resonancia Magnética , Redes y Vías Metabólicas , Metaboloma/efectos de los fármacosRESUMEN
Cytochrome P450 (P450) induction is one of the factors that can affect the pharmacokinetics of a drug molecule upon multiple dosing, and it can result in pharmacokinetic drug-drug interactions with coadministered drugs causing potential therapeutic failures. In recent years, various in vitro assays have been developed and used routinely to assess the potential for drug-drug interactions due to P450 induction. There is a desire from the pharmaceutical industry and regulatory agencies to harmonize assay methodologies, data interpretation, and the design of clinical drug-drug interaction studies. In this article, a team of 10 scientists from nine Pharmaceutical Research and Manufacturers of America (PhRMA) member companies conducted an anonymous survey among PhRMA companies to query current practices with regards to the conduct of in vitro induction assays, data interpretation, and clinical induction study practices. The results of the survey are presented in this article, along with reviews of current methodologies of in vitro assays and in vivo studies, including modeling efforts in this area. A consensus recommendation regarding common practices for the conduct of P450 induction studies is included.
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Sistema Enzimático del Citocromo P-450/biosíntesis , Hepatocitos/metabolismo , Receptores de Esteroides/metabolismo , Américas , Biología Computacional , Sistema Enzimático del Citocromo P-450/metabolismo , Recolección de Datos , Evaluación Preclínica de Medicamentos , Industria Farmacéutica , Interacciones Farmacológicas , Inducción Enzimática/fisiología , Predicción , Humanos , Receptor X de Pregnano , Receptores de Esteroides/genética , Proyectos de Investigación , Activación TranscripcionalRESUMEN
The discovery of novel analgesic compounds that target some receptors can be challenging due to species differences in ligand pharmacology. If a putative analgesic compound has markedly lower affinity for rodent versus other mammalian orthologs of a receptor, the evaluation of antinociceptive efficacy in non-rodent species becomes necessary. Here, we describe a new, efficient method for measuring inflammation-associated nociception in conscious rabbits. An electronic von Frey device is used, consisting of a rigid plastic tip connected to a force transducer in a hand-held probe. The plastic tip is applied to the plantar surface of a hind paw with increasing force until a withdrawal response is observed. The maximum force (g) tolerated by the rabbit (i.e., withdrawal threshold) is recorded. In young, conscious rabbits (500-700 g), baseline hind paw withdrawal thresholds typically fell within the 60-80 g range. Three hours after injection of the inflammatory agent carrageenan (3%, 200 microL, intra-plantar), withdrawal thresholds dropped by approximately 30-40 g, indicating the presence of punctate mechanical hyperalgesia. The development of hyperalgesia was dose dependently prevented by the NSAID indomethacin (ED50=2.56 mg/kg, p.o.) or the bradykinin B2 receptor peptide antagonist HOE 140 (intra-paw administration). An established hyperalgesia was dose dependently reversed by morphine sulfate (ED50=0.096 mg/kg, s.c.) or the bradykinin B1 receptor peptide antagonist [des-Arg10, Leu9]-kallidin (ED50=0.45 mg/kg, s.c.). Rabbits treated with the novel B(1) receptor small molecule antagonist compound A also showed dose-dependent reversal of hyperalgesia (ED50=20.19 mg/kg, s.c.) and analysis of plasma samples taken from these rabbits showed that, unlike other rabbit pain models, the current method permits the evaluation of pharmacokinetic-pharmacodynamic (PK-PD) relationships (compound A plasma EC50=402.6 nM). We conclude that the Electrovonfrey method can be used in rabbits with inflammatory pain to generate reliable dose- and plasma concentration-effect curves for different classes of analgesics.
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Hiperalgesia/etiología , Hiperalgesia/patología , Metacarpo/fisiopatología , Dimensión del Dolor/métodos , Dolor/complicaciones , Análisis de Varianza , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Bradiquinina/administración & dosificación , Bradiquinina/análogos & derivados , Carragenina , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Éteres/sangre , Hidrocarburos Fluorados/sangre , Hiperalgesia/prevención & control , Indometacina/administración & dosificación , Inflamación/inducido químicamente , Inflamación/complicaciones , Calidina/administración & dosificación , Calidina/análogos & derivados , Metacarpo/efectos de los fármacos , Dolor/etiología , Dimensión del Dolor/instrumentación , Umbral del Dolor/efectos de los fármacos , Conejos , Tiempo de Reacción/efectos de los fármacos , Análisis Espectral , Factores de TiempoRESUMEN
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Dolor/tratamiento farmacológico , Sulfonas/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Enfermedad Crónica , Humanos , Conejos , Ratas , Ratas Sprague-Dawley , Sulfonas/administración & dosificaciónRESUMEN
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED(50) = 16.3 mg/kg).
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Bencimidazoles/síntesis química , Benzoxazoles/síntesis química , Piridinas/síntesis química , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Disponibilidad Biológica , Permeabilidad Capilar/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Células Endoteliales/citología , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Venas Umbilicales/citología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
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Amidas/síntesis química , Analgésicos/síntesis química , Benzopiranos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Sulfonamidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Presión Sanguínea/efectos de los fármacos , Células CHO , Calcio/metabolismo , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Masculino , Microsomas/metabolismo , Dolor/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B1/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
The present study investigated the effect of renal impairment and hemodialysis on the pharmacokinetics of lenalidomide following a single 25-mg oral dose in 30 subjects aged 39 to 76 years. A single 25-mg dose was well tolerated by renally impaired subjects. Renal impairment did not alter the oral absorption, protein binding, or nonrenal elimination of lenalidomide. Mean urinary recovery of unchanged lenalidomide was 84% of the dose in subjects with normal renal function (creatinine clearance [CL(Cr)] > 80 mL/min), and it declined to 69%, 38%, and 43% in subjects with mild (50 < or = CL(Cr) < or = 80 mL/min), moderate (30 < or = CL(Cr) < 50 mL/min), and severe (CL(Cr) < 30 mL/min) renal impairment, respectively. The differences in pharmacokinetic parameters between normal renal function and mild renal impairment were minor to modest (11%-32%). As renal impairment progressed to moderate, severe, or end-stage renal disease, total and renal lenalidomide clearance decreased drastically, area under the concentration-time curve increased by approximately 185% to 420%, and t((1/2)) was prolonged by approximately 6 to 12 hours. A 4-hour hemodialysis removed 31% of lenalidomide in the body. Therefore, lenalidomide dose adjustments should be considered for patients with CL(Cr) < 50 mL/min, and the recommendations are given for the starting doses.
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Fallo Renal Crónico/fisiopatología , Diálisis Renal , Talidomida/análogos & derivados , Administración Oral , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Área Bajo la Curva , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/terapia , Lenalidomida , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Estereoisomerismo , Espectrometría de Masas en Tándem , Talidomida/química , Talidomida/farmacocinéticaRESUMEN
BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs. Among various types of cancer, metastatic prostate cancer is an area of high unmet medical need with minimal therapeutic options. Recently, enzalutamide was approved for treatment of metastatic prostate cancer and is often dosed as a combination in clinical practice. Enzalutamide is a potent CYP3A inducer and a model-based approach to guide dose-selection for enzalutamide combinations that are CYP3A substrates is needed. OBJECTIVE: A "fit for purpose" PBPK model of enzalutamide was developed to illustrate the CYP3A4 induction potential, understand the kinetics of de-induction of CYP3A4 following cessation of enzalutamide dosing and guide dose-selection of a co-administered CYP3A substrate. METHOD: The population-based simulator, Simcyp, was used for model building purposes. Model input parameters were obtained from public information, primarily from the FDA summaries. RESULTS: The simulated concentration time profiles of enzalutamide in healthy male subjects were comparable to observed profiles in male patients. Model predicted enzalutamide pharmacokinetic (PK) parameters, i.e. AUC, Cmax and half-life were within 1.5-fold of observed results obtained from two reported studies, supporting verification of the PBPK model. Model application was demonstrated by simulating a drug-drug interaction between enzalutamide and midazolam, a sensitive CYP3A4 substrate. Based on simulations, the midazolam AUC ratio ranged from 0.06 to 0.16 and was comparable to the observed ratio of 0.14. Based on modeling, upon cessation of enzalutamide dosing, it is predicted that at least 8 weeks are needed to re-attain baseline CYP3A4 activity. Based on PBPK modeling, dose adjustment of up to 3-fold for a co-administered CYP3A substrate was shown to re-attain baseline exposure. CONCLUSION: A "fit for purpose" PBPK model of enzalutamide was successfully developed using public information that recapitulated it's observed pharmacokinetics, CYP3A4 induction potential and the potential need for dose-adjustment of co-administered CYP3A substrates.
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Antineoplásicos/administración & dosificación , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Modelos Biológicos , Feniltiohidantoína/análogos & derivados , Adulto , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Área Bajo la Curva , Benzamidas , Simulación por Computador , Citocromo P-450 CYP3A/biosíntesis , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Semivida , Humanos , Masculino , Midazolam/farmacocinética , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/farmacocinética , Feniltiohidantoína/farmacología , Factores de Tiempo , Adulto JovenRESUMEN
Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.
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Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Talidomida/análogos & derivados , Adulto , Animales , Carbamazepina/farmacología , Línea Celular , Interacciones Farmacológicas , Fluvoxamina/farmacología , Células HEK293 , Voluntarios Sanos , Humanos , Cetoconazol/farmacología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Porcinos , Talidomida/farmacocinética , Talidomida/farmacología , Adulto JovenRESUMEN
Current regulatory guidances do not address specific study designs for in vitro and in vivo drug-drug interaction studies. There is a common desire by regulatory authorities and by industry sponsors to harmonize approaches to allow for a better assessment of the significance of findings across different studies and drugs. There is also a growing consensus for the standardization of cytochrome P450 (CYP) probe substrates, inhibitors, and inducers and for the development of classification systems to improve the communication of risk to health care providers and patients. While existing guidances cover mainly CYP-mediated drug interactions, the importance of other mechanisms, such as transporters, has been recognized more recently and should also be addressed. This paper was prepared by the Pharmaceutical Research and Manufacturers of America (PhRMA) Drug Metabolism and Clinical Pharmacology Technical Working Groups and represents the current industry position. The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to define a data package that can be expected by regulatory agencies in compound registration dossiers.