RESUMEN
To enable the clinical development of our CNS casein kinase 1 delta/epsilon (CK1δ/ε) inhibitor project, we investigated the possibility of developing a CNS positron emission tomography (PET) radioligand. For this effort, we focused our design and synthesis efforts on the initial CK1δ/ε inhibitor HTS hits with the goal of identifying a compound that would fulfill a set of recommended PET ligand criteria. We identified [3H]PF-5236216 (9) as a tool ligand that meets most of the key CNS PET attributes including high CNS MPO PET desirability score and kinase selectivity, CNS penetration, and low nonspecific binding. We further used [3H]-9 to determine the binding affinity for PF-670462, a literature CK1δ/ε inhibitor tool compound. Lastly, [3H]-9 was used to measure in vivo target occupancy (TO) of PF-670462 in mouse and correlated TO with CK1δ/ε in vivo pharmacology (circadian rhythm modulation).
Asunto(s)
Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Quinasa de la Caseína I/antagonistas & inhibidores , Lactamas , Tomografía de Emisión de Positrones , Radiofármacos , Animales , Células COS , Quinasa de la Caseína I/metabolismo , Chlorocebus aethiops , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Diseño de Fármacos , Humanos , Lactamas/síntesis química , Lactamas/farmacocinética , Masculino , Ratones Endogámicos C57BL , Estructura Molecular , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Distribución AleatoriaRESUMEN
Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.
Asunto(s)
Analgésicos Opioides/efectos adversos , Antagonistas de los Receptores de Dopamina D2/química , Antagonistas de los Receptores de Dopamina D2/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Receptores de Dopamina D3/antagonistas & inhibidores , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Animales , Línea Celular Transformada , Condicionamiento Operante/efectos de los fármacos , Dopaminérgicos/farmacología , Relación Dosis-Respuesta a Droga , Fentanilo/efectos adversos , Humanos , Masculino , Neuroblastoma/patología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Autoadministración , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
An approach to the synthesis of sulfonamides from sulfamoyl inner salts and organometallic species is presented. A range of sulfamoyl carbamates, amines, and metals are explored. Primary, secondary, and tertiary alkyl-, aryl-, and heteroaryllitihium and magnesium nucleophiles were successful. This approach yields bench-stable intermediates and avoids many of the functional group incompatibilities, regioselectivity issues, and high-energy reagents generally associated with the synthesis of sulfonamides. Additionally, the products may be purified by basic extraction or salt formation, avoiding chromatography.
Asunto(s)
Carbamatos/química , Compuestos Organometálicos/química , Sulfonamidas/síntesis química , Catálisis , Indicadores y Reactivos/química , Estructura Molecular , Sulfonamidas/químicaRESUMEN
Casein kinase 1 delta (CK1δ) and casein kinase 1 epsilon (CK1ε) inhibitors are potential therapeutic agents for a range of psychiatric disorders. The feasibility of developing a CNS kinase inhibitor has been limited by an inability to identify safe brain-penetrant compounds with high kinome selectivity. Guided by structure-based drug design, potent and selective CK1δ/ε inhibitors have now been identified that address this gap, through the design and synthesis of novel 4-[4-(4-fluorophenyl)-1-(piperidin-4-yl)-1H-imidazol-5-yl]pyrimidin-2-amine derivatives. PF-5006739 (6) possesses a desirable profile, with low nanomolar in vitro potency for CK1δ/ε (IC50 = 3.9 and 17.0 nM, respectively) and high kinome selectivity. In vivo, 6 demonstrated robust centrally mediated circadian rhythm phase-delaying effects in both nocturnal and diurnal animal models. Further, 6 dose-dependently attenuated opioid drug-seeking behavior in a rodent operant reinstatement model in animals trained to self-administer fentanyl. Collectively, our data supports further development of 6 as a promising candidate to test the hypothesis of CK1δ/ε inhibition in treating multiple indications in the clinic.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Quinasa de la Caseína I/antagonistas & inhibidores , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Fentanilo/administración & dosificación , Análisis de Varianza , Animales , Ritmo Circadiano/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/química , Humanos , Isoxazoles/farmacología , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Transporte de Proteínas/efectos de los fármacos , Pirimidinas/farmacología , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Autoadministración , Factores de TiempoRESUMEN
A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters.
Asunto(s)
Descubrimiento de Drogas/métodos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Animales , Fármacos del Sistema Nervioso Central/efectos adversos , Perros , Humanos , Lípidos/química , Macaca fascicularis , Nivel sin Efectos Adversos Observados , RatasRESUMEN
Csnk1e, the gene encoding casein kinase 1-epsilon, has been implicated in sensitivity to amphetamines. Additionally, a polymorphism in CSNK1E was associated with heroin addiction, suggesting that this gene may also affect opioid sensitivity. In this study, we first conducted genome-wide quantitative trait locus (QTL) mapping of methamphetamine (MA)-induced locomotor activity in C57BL/6J (B6) × DBA/2J (D2)-F(2) mice and a more highly recombinant F(8) advanced intercross line. We identified a QTL on chromosome 15 that contained Csnk1e (63-86 Mb; Csnk1e=79.25 Mb). We replicated this result and further narrowed the locus using B6.D2(Csnk1e) and D2.B6(Csnk1e) reciprocal congenic lines (78-86.8 and 78.7-81.6 Mb, respectively). This locus also affected sensitivity to the µ-opioid receptor agonist fentanyl. Next, we directly tested the hypothesis that Csnk1e is a genetic regulator of sensitivity to psychostimulants and opioids. Mice harboring a null allele of Csnk1e showed an increase in locomotor activity following MA administration. Consistent with this result, coadministration of a selective pharmacological inhibitor of Csnk1e (PF-4800567) increased the locomotor stimulant response to both MA and fentanyl. These results show that a narrow genetic locus that contains Csnk1e is associated with differences in sensitivity to MA and fentanyl. Furthermore, gene knockout and selective pharmacological inhibition of Csnk1e define its role as a negative regulator of sensitivity to psychostimulants and opioids.
Asunto(s)
Analgésicos Opioides/farmacología , Caseína Cinasa 1 épsilon/genética , Estimulantes del Sistema Nervioso Central/farmacología , Resistencia a Medicamentos/genética , Sitios de Carácter Cuantitativo/genética , Animales , Caseína Cinasa 1 épsilon/deficiencia , Femenino , Estudio de Asociación del Genoma Completo/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genéticaRESUMEN
As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.