RESUMEN
As a follow-up to the GPR40 agonist AMG 837, which was evaluated in clinical trials for the treatment of type II diabetes, further optimization led to the discovery of AM-3189 (13k). AM-3189 is representative of a new class of compounds with minimal CNS penetration, superior pharmacokinetic properties and in vivo efficacy comparable to AMG 837.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Macaca fascicularis , Ratones , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Polo like kinase 2 (PLK2) phosphorylates α-synuclein and is considered a putative therapeutic target for Parkinson's disease. Several lines of evidence indicate that PLK2 is involved with proper centriole duplication and cell cycle regulation, inhibition of which could impact chromosomal integrity during mitosis. The objectives of the series of experiments presented herein were to assess whether specific inhibition of PLK2 is genotoxic and determine if PLK2 could be considered a tractable pharmacological target for Parkinson's disease. Several selective PLK2 inhibitors, ELN 582175 and ELN 582646, and their inactive enantiomers, ELN 582176 and ELN 582647, did not significantly increase the number of micronuclei in the in vitro micronucleus assay. ELN 582646 was administered to male Sprague Dawley rats in an exploratory 14-day study where flow cytometric analysis of peripheral blood identified a dose-dependent increase in the number of micronucleated reticulocytes. A follow-up investigative study demonstrated that ELN 582646 administered to PLK2 deficient and wildtype mice significantly increased the number of peripheral micronucleated reticulocytes in both genotypes, suggesting that ELN 582646-induced genotoxicity is not through the inhibition of PLK2. Furthermore, significant reduction of retinal phosphorylated α-synuclein levels was observed at three non-genotoxic doses, additional data to suggest that pharmacological inhibition of PLK2 is not the cause of the observed genotoxicity. These data, in aggregate, indicate that PLK2 inhibition is a tractable CNS pharmacological target that does not cause genotoxicity at doses and exposures that engage the target in the sensory retina.
Asunto(s)
Aberraciones Cromosómicas/inducido químicamente , Linfocitos/efectos de los fármacos , Micronúcleos con Defecto Cromosómico/inducido químicamente , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Reticulocitos/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Citometría de Flujo , Células HEK293 , Humanos , Linfocitos/enzimología , Linfocitos/patología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Pruebas de Micronúcleos , Fosforilación , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Reticulocitos/enzimología , Reticulocitos/patología , Retina/efectos de los fármacos , Retina/metabolismo , Medición de Riesgo , Factores de Tiempo , Transfección , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMEN
Sitaxentan is a selective endothelin-A receptor antagonist that was marketed as Thelin in several European countries and Canada for pulmonary arterial hypertension. Sitaxentan was undergoing further clinical trials in the United States but due to four deaths and one case of liver transplantation from severe liver toxicity that appeared to be idiosyncratic in nature, it was withdrawn worldwide in December, 2010. Sitaxentan contains a 1,3-benzodioxole ring that undergoes enzymatic demethyleneation to an ortho-catechol metabolite that can further oxidize to a reactive ortho-quinone metabolite. Here, we report the detection and mass spectral characterization of a glutathione conjugate of this sitaxentan quinone reactive metabolite that was trapped in vitro using mouse, rat, dog, and human liver microsomes supplemented with NADPH and glutathione and that was also observed in rat and human hepatocytes. Using human liver microsomes, we also demonstrated that P450 3A4 undergoes time-dependent inhibition. Density functional calculations on the catechol metabolite of sitaxentan indicated that the reaction leading to the quinone was thermodynamically favorable with an enthalpy change of -6.3 kcal/mol. Using density functional methodology, we modeled the attack of glutathione on the quinone with an S-methyl thiolate anion which allowed us to predict, based on the difference in transition state energies, that the 2-position on the phenyl ring was more likely than the 5-position as the site of glutathione conjugation. Overall, our results demonstrated that sitaxentan is capable of facile formation of a reactive ortho-quinone metabolite capable of reacting with glutathione and may rationalize the idiosyncratic nature of the hepatotoxicity that led to its withdrawal.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Glutatión/química , Hepatocitos/metabolismo , Isoxazoles/metabolismo , Isoxazoles/toxicidad , Microsomas Hepáticos/metabolismo , Tiofenos/metabolismo , Tiofenos/toxicidad , Animales , Benzoquinonas/química , Benzoquinonas/metabolismo , Biotransformación , Catecoles/química , Catecoles/metabolismo , Cromatografía Liquida , Sistema Enzimático del Citocromo P-450/biosíntesis , Perros , Humanos , Isoxazoles/efectos adversos , Isoxazoles/química , Ratones , Teoría Cuántica , Ratas , Espectrometría de Masas en Tándem , Tiofenos/efectos adversos , Tiofenos/químicaRESUMEN
Structure-activity relationship (SAR) of a novel, potent and metabolically stable series of benzo [3.2.1] bicyclic sulfonamide-pyrazoles as γ-secretase inhibitors are described. Compounds that are efficacious in reducing the cortical Aßx-40 levels in FVB mice via oral dose, as well as those with high selectivity over Notch, are highlighted.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Pirazoles/farmacología , Sulfonamidas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ratones , Pirazoles/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson's disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41-45% reduction of pS129-α-synuclein levels in the cerebral cortex.
Asunto(s)
Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Administración Oral , Animales , Encéfalo/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Células HEK293 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Pteridinas/síntesis química , Pteridinas/química , Pteridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Quinasa Tipo Polo 1RESUMEN
CYP3A4-mediated biotransformation of (R)-N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl)ethyl)-N-(pyridin-3-ylmethyl)-2-(4-(trifluoromethoxy)phenyl)acetamide (AMG 487) was previously shown to generate an inhibitory metabolite linked to dose- and time-dependent pharmacokinetics in humans. Although in vitro activity loss assays failed to demonstrate CYP3A4 time-dependent inhibition (TDI) with AMG 487, its M2 phenol metabolite readily produced TDI when remaining activity was assessed using either midazolam or testosterone (K(I) = 0.73-0.74 µM, k(inact) = 0.088-0.099 min(-1)). TDI investigations using an IC(50) shift method successfully produced inhibition attributable to AMG 487, but only when preincubations were extended from 30 to 90 min. The shift magnitude was â¼3× for midazolam activity, but no shift was observed for testosterone activity. Subsequent partition ratio determinations conducted for M2 using recombinant CYP3A4 showed that inactivation was a relatively inefficient process (r = 36). CYP3A4-mediated biotransformation of [(3)H]M2 in the presence of GSH led to identification of two new metabolites, M4 and M5, which shifted focus away from M2 being directly responsible for TDI. M4 (hydroxylated M2) was further metabolized to form reactive intermediates that, upon reaction with GSH, produced isomeric adducts, collectively designated M5. Incubations conducted in the presence of [(18)O]H(2)O confirmed incorporation of oxygen from O(2) for the majority of M4 and M5 formed (>75%). Further evidence of a primary role for M4 in CYP3A4 TDI was generated by protein labeling and proteolysis experiments, in which M4 was found to be covalently bound to Cys239 of CYP3A4. These investigations confirmed a primarily role for M4 in CYP3A4 inactivation, suggesting that a more complex metabolic pathway was responsible for generation of inhibitory metabolites affecting AMG 487 human pharmacokinetics.
Asunto(s)
Acetamidas/farmacología , Acetamidas/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Pirimidinonas/farmacología , Pirimidinonas/farmacocinética , Receptores CXCR3/antagonistas & inhibidores , Biotransformación , Humanos , Redes y Vías Metabólicas , Microsomas Hepáticos/metabolismo , Midazolam/metabolismo , Midazolam/farmacocinética , Oxígeno/metabolismo , Proteolisis , Quinonas/farmacocinética , Receptores CXCR3/metabolismo , Testosterona/metabolismo , Testosterona/farmacocinéticaRESUMEN
The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
Asunto(s)
Quinazolinas/síntesis química , Quinazolinonas/síntesis química , Receptores CXCR3/antagonistas & inhibidores , Animales , Bleomicina/toxicidad , Aberraciones Cromosómicas , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Perros , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Inflamación , Concentración 50 Inhibidora , Leucocitos/efectos de los fármacos , Macaca fascicularis , Ratones , Modelos Químicos , Quinazolinas/farmacología , Quinazolinonas/farmacología , Factores de TiempoRESUMEN
The discovery that certain long chain fatty acids potentiate glucose stimulated insulin secretion through the previously orphan receptor GPR40 sparked interest in GPR40 agonists as potential antidiabetic agents. Optimization of a series of ß-substituted phenylpropanoic acids led to the identification of (S)-3-(4-((4'-(trifluoromethyl)biphenyl-3-yl)methoxy)phenyl)hex-4-ynoic acid (AMG 837) as a potent GPR40 agonist with a superior pharmacokinetic profile and robust glucose-dependent stimulation of insulin secretion in rodents.
Asunto(s)
Compuestos de Bifenilo/farmacología , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Estructura Molecular , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.
Asunto(s)
Encéfalo/metabolismo , Diseño de Fármacos , Degeneración Nerviosa/prevención & control , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Tiofenos/farmacología , Tiofenos/farmacocinética , Animales , Técnicas de Química Sintética , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Semivida , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/químicaRESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our efforts at further optimization of this series, culminating in 2 with submicromolar potency in a HWB assay and efficacy in a CIA mouse model.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Quinolinas/química , Semicarbacidas/química , Tiourea/análogos & derivados , Animales , Perros , Femenino , Hepatocitos/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Quinasa I-kappa B/metabolismo , Macaca mulatta , Masculino , Ratones , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Semicarbacidas/síntesis química , Semicarbacidas/farmacocinética , Relación Estructura-Actividad , Tiourea/síntesis química , Tiourea/química , Tiourea/farmacocinéticaRESUMEN
A novel series of (E)-1-((2-(1-methyl-1H-imidazol-5-yl) quinolin-4-yl) methylene) thiosemicarbazides was discovered as potent inhibitors of IKKß. In this Letter we document our early efforts at optimization of the quinoline core, the imidazole and the semithiocarbazone moiety. Most potency gains came from substitution around the 6- and 7-positions of the quinoline ring. Replacement of the semithiocarbazone with a semicarbazone decreased potency but led to some measurable exposure.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Semicarbacidas/química , Animales , Perros , Femenino , Ensayos Analíticos de Alto Rendimiento , Quinasa I-kappa B/metabolismo , Masculino , Microsomas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Quinolinas/química , Ratas , Semicarbacidas/síntesis química , Semicarbacidas/farmacocinética , Relación Estructura-ActividadRESUMEN
The 2-methyl substituted indole, 2MI [2-(4-(4-(2,4-dichlorophenylsulfonamido)-2-methyl-1H-indol-5-yloxy)-3-methoxyphenyl)acetic acid] is a potent dual inhibitor of 1) chemoattractant receptor-homologous molecule expressed on T-helper type-2 cells and 2) d-prostanoid receptor. During evaluation as a potential treatment for asthma and allergic rhinitis, 2MI was identified as a mechanism-based inactivator of CYP3A4 in vitro. The inactivation was shown to be irreversible by dialysis and accompanied by an NADPH-dependent increase in 2MI covalent binding to a 55- to 60-kDa microsomal protein, consistent with irreversible binding to CYP3A4. Two glutathione (GSH) adducts, G1 and G2, were identified in vitro, and the more abundant adduct (G1) was unambiguously determined via NMR to be GSH adducted to the 3-position of the 2-methylindole moiety. The potential for a clinical drug-drug interaction arising from mechanism-based inactivation of CYP3A4 by 2MI was predicted using a steady-state model, and a 4.3- to 7.5-fold increase in the exposure of midazolam was predicted at anticipated therapeutic concentrations. To better assess the potential for in vivo drug-drug interactions, the Sprague-Dawley rat was used as an in vivo model. An excellent in vitro-in vivo correlation was observed for the reduction in enzyme steady-state concentration (E'(ss/Ess)) as well as the change in the exposure of a prototypical CYP3A substrate, indinavir (area under the curve (AUC) for indinavir/AUC). In summary, 2MI was identified as a potent mechanism-based inactivator of CYP3A and was predicted to elicit a clinically relevant drug-drug interaction in humans at an anticipated therapeutic concentration.
Asunto(s)
Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Glutatión/metabolismo , Indoles/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/efectos de los fármacos , Hidrocarburo de Aril Hidroxilasas/metabolismo , Biocatálisis/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Peroxidasa de Rábano Silvestre/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Indinavir/metabolismo , Indinavir/farmacocinética , Indoles/farmacología , Cinética , Espectroscopía de Resonancia Magnética , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Midazolam/metabolismo , Midazolam/farmacocinética , Modelos Biológicos , Estructura Molecular , NADP/metabolismo , Farmacocinética , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en TándemRESUMEN
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and multiple sclerosis. Inhibition of RIPK1 activity protects against inflammation and cell death in multiple animal models. DNL104 is a selective, brain-penetrant inhibitor of RIPK1 phosphorylation in clinical development for AD and ALS. DNL104 was tested in 68 healthy volunteers to investigate safety and tolerability, pharmacokinetic profile in plasma and cerebrospinal fluid, and pharmacodynamic effects of RIPK1 inhibition in peripheral blood mononuclear cells in a first-in-human, placebo-controlled, double-blind, randomized single-ascending dose (SAD) and multiple-ascending dose (MAD) study. DNL104 was well-tolerated in the SAD group and during the dosing period of the MAD group. However, postdose liver toxicity in 37.5% of subjects was observed in the MAD, and assessed to be drug related. We demonstrate that DNL104 leads to RIP1 kinase inhibition, and this is not associated with central nervous system (CNS) toxicities, supporting future development of CNS penetrant RIPK1 inhibitors.
Asunto(s)
Proteína Serina-Treonina Quinasas de Interacción con Receptores/antagonistas & inhibidores , Adolescente , Adulto , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Semivida , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Fosforilación/efectos de los fármacos , Adulto JovenRESUMEN
(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharmacokinetics on both days 1 and 7 at the 25-mg dose, dose- and time-dependent kinetics were evident at the two higher doses. Nonlinear kinetics were more pronounced after multiple dosing. Area under the plasma concentration-time curve from 0 to 24 h [AUC((0-24 h))] increased 96-fold with a 10-fold increase in dose on day 7 compared with a 28-fold increase in AUC((0-24 h)) on day 1. These changes were correlated with time- and dose-dependent decreases in the metabolite to parent plasma concentrations, suggesting that these changes result from a decrease in the oral clearance (CL) of AMG 487 (e.g., intestinal/hepatic first-pass metabolism and systemic CL). The biotransformation of AMG 487 is dependent on CYP3A and results in the formation of two primary metabolites, a pyridyl N-oxide AMG 487 (M1) and an O-deethylated AMG 487 (M2). One of these metabolites, M2, undergoes further metabolism by CYP3A. M2 has also been demonstrated to inhibit CYP3A in a competitive (K(i)=0.75 microM) manner as well as via mechanism-based inhibition (unbound K(I)=1.4 microM, k(inact)=0.041 min(-1)). Data from this study implicate M2-mediated CYP3A mechanism-based inhibition as the proximal cause for the time-dependent pharmacokinetics of AMG 487. However, the sequential metabolism of M2, nonlinear AMG 487 pharmacokinetics, and the inability to accurately determine the role of intestinal AMG 487 metabolism complicates the correlation between M2 plasma concentrations and the time-dependent AMG 487 pharmacokinetic changes.
Asunto(s)
Acetamidas/farmacocinética , Pirimidinonas/farmacocinética , Receptores CXCR3/antagonistas & inhibidores , Acetamidas/administración & dosificación , Adulto , Área Bajo la Curva , Cromatografía Liquida , Estudios de Cohortes , Inhibidores Enzimáticos del Citocromo P-450 , Esquema de Medicación , Humanos , Masculino , Pirimidinonas/administración & dosificación , Espectrometría de Masas en TándemRESUMEN
Time-dependent inhibition (TDI) of cytochrome P450 (P450) enzymes caused by new molecular entities (NMEs) is of concern because such compounds can be responsible for clinically relevant drug-drug interactions (DDI). Although the biochemistry underlying mechanism-based inactivation (MBI) of P450 enzymes has been generally understood for several years, significant advances have been made only in the past few years regarding how in vitro time-dependent inhibition data can be used to understand and predict clinical DDI. In this article, a team of scientists from 16 pharmaceutical research organizations that are member companies of the Pharmaceutical Research and Manufacturers of America offer a discussion of the phenomenon of TDI with emphasis on the laboratory methods used in its measurement. Results of an anonymous survey regarding pharmaceutical industry practices and strategies around TDI are reported. Specific topics that still possess a high degree of uncertainty are raised, such as parameter estimates needed to make predictions of DDI magnitude from in vitro inactivation parameters. A description of follow-up mechanistic experiments that can be done to characterize TDI are described. A consensus recommendation regarding common practices to address TDI is included, the salient points of which include the use of a tiered approach wherein abbreviated assays are first used to determine whether NMEs demonstrate TDI or not, followed by more thorough inactivation studies for those that do to define the parameters needed for prediction of DDI.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Industria Farmacéutica , Interacciones Farmacológicas , Microsomas Hepáticos/metabolismo , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP3A/metabolismo , Diseño de Fármacos , Glucuronosiltransferasa , Humanos , Microsomas Hepáticos/enzimología , Oxidorreductasas N-Desmetilantes/metabolismo , Preparaciones Farmacéuticas/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato , Factores de TiempoRESUMEN
The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
Asunto(s)
Antiinflamatorios/química , Pirimidinonas/química , Quinazolinonas/química , Receptores CXCR3/antagonistas & inhibidores , Sulfonas/química , Acetamidas/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Movimiento Celular , Perros , Haplorrinos , Humanos , Ratones , Pirimidinonas/síntesis química , Pirimidinonas/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Ratas , Receptores CXCR3/metabolismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
A series of tetrahydroquinoline-derived inhibitors of the CRTH2 receptor was discovered by a high throughput screen. Optimization of these compounds for potency and pharmacokinetic properties led to the discovery of potent and orally bioavailable CRTH2 antagonists.
Asunto(s)
Antialérgicos/química , Quinolinas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Antialérgicos/farmacocinética , Antialérgicos/farmacología , Línea Celular , Forma de la Célula/efectos de los fármacos , Descubrimiento de Drogas , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Humanos , Quinolinas/farmacocinética , Quinolinas/farmacologíaRESUMEN
A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties. These efforts led to selection of AMG 009 as a clinical candidate.
Asunto(s)
Asma/metabolismo , Receptores de Prostaglandina/química , Animales , Diseño de Fármacos , Humanos , Receptores de Prostaglandina/clasificación , Relación Estructura-Actividad , Células Th2/metabolismoRESUMEN
A general way of improving the potency of CXCR3 antagonists with fused hetero-bicyclic cores was identified. Optimization efforts led to the discovery of a series of imidazo-pyrazine derivatives with improved pharmacokinetic properties in addition to increased potency. The efficacy of the lead compound 21 is evaluated in a mouse lung inflammation model.
Asunto(s)
Antiinflamatorios/química , Bencenoacetamidas/química , Óxidos S-Cíclicos/química , Imidazoles/química , Pirazinas/química , Receptores CXCR3/antagonistas & inhibidores , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacocinética , Bencenoacetamidas/síntesis química , Bencenoacetamidas/farmacocinética , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacocinética , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Ratones , Conformación Molecular , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas , Receptores CXCR3/metabolismoRESUMEN
A series of imidazole derivatives have been designed and optimized for CXCR3 antagonism, pharmacokinetic properties, and reduced formation of glutathione conjugates. Our efforts led to the discovery of potent CXCR3 antagonists with good pharmacokinetic properties. These compounds are useful tools for in vivo studies of CXCR3 function.