RESUMEN
Facilitating activation, or delaying inactivation, of the native Kv7 channel reduces neuronal excitability, which may be beneficial in controlling spontaneous electrical activity during epileptic seizures. In an effort to identify a compound with such properties, the structure-activity relationship (SAR) and in vitro ADME for a series of heterocyclic Kv7.2-7.5 channel openers was explored. PF-05020182 (2) demonstrated suitable properties for further testing in vivo where it dose-dependently decreased the number of animals exhibiting full tonic extension convulsions in response to corneal stimulation in the maximal electroshock (MES) assay. In addition, PF-05020182 (2) significantly inhibited convulsions in the MES assay at doses tested, consistent with in vitro activity measure. The physiochemical properties, in vitro and in vivo activities of PF-05020182 (2) support further development as an adjunctive treatment of refractory epilepsy.
Asunto(s)
Descubrimiento de Drogas , Epilepsia/tratamiento farmacológico , Activación del Canal Iónico/efectos de los fármacos , Canal de Potasio KCNQ2/metabolismo , Piperidinas/farmacología , Pirimidinas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Electrochoque , Humanos , Canal de Potasio KCNQ2/agonistas , Microsomas/efectos de los fármacos , Estructura Molecular , Piperidinas/administración & dosificación , Piperidinas/química , Pirimidinas/administración & dosificación , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Herein we report the identification of (+)-N-(2-((1H-pyrazol-1-yl)methyl)-3-((1R,3r,5S)-6'-fluoro-8-azaspiro[bicyclo[3.2.1]octane-3,1'-isochroman]-8-yl)propyl)-N-[(3)H]-methylacetamide {[(3)H]PF-7191 [(+)-11]} as a promising radiotracer for the nociceptin opioid peptide (NOP) receptor. (+)-11 demonstrated high NOP binding affinity (Ki = 0.1 nM), excellent selectivity over other opioid receptors (>1000×) and good brain permeability in rats (C(b,u)/C(p,u) = 0.29). Subsequent characterization of [(3)H](+)-11 showed a high level of specific binding and a brain bio-distribution pattern consistent with known NOP receptor expression. Furthermore, the in vivo brain binding of [(3)H](+)-11 in rats was inhibited by a selective NOP receptor antagonist in a dose-responsive manner. This overall favorable profile indicated that [(3)H](+)-11 is a robust radiotracer for pre-clinical in vivo receptor occupancy (RO) measurements and a possible substrate for carbon-11 labeling for positron emission tomography (PET) imaging in higher species.
Asunto(s)
Encéfalo/metabolismo , Diseño de Fármacos , Péptidos Opioides/metabolismo , Receptores Opioides/metabolismo , Tritio/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Péptidos Opioides/química , Unión Proteica/fisiología , Ratas , Tritio/química , Receptor de NociceptinaRESUMEN
We describe a novel series of inhibitors of the type 1 glycine transporter (GlyT1) as an approach to relieving the glutamatergic deficit that is thought to underlie schizophrenia. Synthesis and SAR follow-up of a series of octahydro-cyclopenta[c]pyrrole derivatives afforded potent in vitro inhibition of GlyT1 as well as in vivo activity in elevating CSF glycine. We also found that a 3-O(c-pentyl), 4-F substituent may serve as a surrogate for the widely used 3-trifluoromethoxy group, suggesting its application as an isostere for future medicinal chemistry studies.
Asunto(s)
Ciclopentanos/química , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Pirroles/química , Animales , Línea Celular , Ciclopentanos/farmacología , Perros , Proteínas de Transporte de Glicina en la Membrana Plasmática/fisiología , Humanos , Microsomas/efectos de los fármacos , Microsomas/fisiología , Pirroles/farmacologíaRESUMEN
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Receptor del Glutamato Metabotropico 5/metabolismo , Animales , Femenino , Células HEK293 , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Masculino , Simulación del Acoplamiento Molecular , Piridinas/efectos adversos , Piridinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.
Asunto(s)
Descubrimiento de Drogas , Quinasas Asociadas a Receptores de Interleucina-1/antagonistas & inhibidores , Isoquinolinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Relación Dosis-Respuesta a Droga , Humanos , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Isoquinolinas/administración & dosificación , Isoquinolinas/química , Lactamas , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
The palladium - catalyzed aminocarbonylation of aryl tosylates with amines is reported. Suitable conditions were identified by high throughput reaction screening and then further optimized. The substrate scope of the reaction with respect to the aryl tosylate component and the amine component are reported. Competitive aminolysis of the aryl tosylates to afford the amine toluenesulfonamides and the phenol was not observed.
Asunto(s)
Aminas/química , Fenilacetatos/síntesis química , Compuestos de Tosilo/química , Catálisis , Estructura Molecular , Paladio/química , Fenilacetatos/químicaRESUMEN
We report that the stereochemical outcome of the conjugate addition of organocopper reagents to bicyclic α,ß-unsaturated lactams derived from pyroglutaminol is determined by the nature of the aminal group. Bicyclic α,ß-unsaturated lactams in which the aminal is derived from a ketone have been found to afford products of syn conjugate addition. By contrast, bicyclic α,ß-unsaturated lactams in which the aminal is derived from an aldehyde afford products of anti conjugate addition. These remarkably different results obtained from very similar starting materials are unexpected.
Asunto(s)
Cobre/química , Lactamas/química , Aldehídos/química , Cetonas/química , Estructura Molecular , Pirroles/química , EstereoisomerismoRESUMEN
The synthesis and structure-activity relationships of a series of 6-phenyl-2-aminopyridines that potently and selectively inhibit the neuronal isoform of nitric oxide synthase (nNOS) are described. Compound 14bi from this series exhibits potent in vivo activity in harmaline-induced cGMP formation in rat cerebellum, a functional model of nNOS inhibition, and in the PCP-induced hypermotility model in the rat. These results suggest that 14bi may be a useful reagent for evaluating potential therapeutic applications of nNOS inhibitors in the central nervous system.
Asunto(s)
Aminopiridinas/síntesis química , Óxido Nítrico Sintasa/antagonistas & inhibidores , Tetrahidronaftalenos/síntesis química , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Cerebelo/efectos de los fármacos , Cerebelo/metabolismo , GMP Cíclico/biosíntesis , Masculino , Actividad Motora/efectos de los fármacos , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa de Tipo I , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrahidronaftalenos/química , Tetrahidronaftalenos/farmacologíaRESUMEN
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Asunto(s)
Pirazinas/síntesis química , Pirazoles/síntesis química , Receptor del Glutamato Metabotropico 5/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Administración Oral , Regulación Alostérica , Animales , Antiparkinsonianos/efectos adversos , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Perros , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Células HEK293 , Humanos , Hipersensibilidad Tardía/inducido químicamente , Levodopa/efectos adversos , Macaca fascicularis , Células de Riñón Canino Madin Darby , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/fisiopatología , Pirazinas/farmacología , Pirazinas/toxicidad , Pirazoles/farmacología , Pirazoles/toxicidad , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
INTRODUCTION: Fatty acid amide hydrolase (FAAH) is responsible for the enzymatic degradation of the fatty acid amide family of signaling lipids, including the endogenous cannabinoid (endocannabinoid) anandamide. The involvement of the endocannabinoid system in pain and other nervous system disorders has made FAAH an attractive target for drug development. Companion molecular imaging probes are needed, however, to assess FAAH inhibition in the nervous system in vivo. We report here the synthesis and in vivo evaluation of [(18)F]PF-9811, a novel PET ligand for non-invasive imaging of FAAH in the brain. METHODS: The potency and selectivity of unlabeled PF-9811 were determined by activity-based protein profiling (ABPP) both in vitro and in vivo. [(18)F]PF-9811 was synthesized in a 3-step, one-pot reaction sequence, followed by HPLC purification. Biological evaluation was performed by biodistribution and dynamic PET imaging studies in male rats. The specificity of [(18)F]PF-9811 uptake was evaluated by pre-administration of PF-04457845, a potent and selective FAAH inhibitor, 1h prior to radiotracer injection. RESULTS: Biodistribution studies show good uptake (SUV~0.8 at 90 min) of [(18)F]PF-9811 in rat brain, with significant reduction of the radiotracer in all brain regions (37%-73% at 90 min) in blocking experiments. Dynamic PET imaging experiments in rat confirmed the heterogeneous uptake of [(18)F]PF-9811 in brain regions with high FAAH enzymatic activity, as well as statistically significant reductions in signal following pre-administration of the blocking compound PF-04457845. CONCLUSIONS: [(18)F]PF-9811 is a promising PET imaging agent for FAAH. Biodistribution and PET imaging experiments show that the tracer has good uptake in brain, regional heterogeneity, and specific binding as determined by blocking experiments with the highly potent and selective FAAH inhibitor, PF-04457845.
Asunto(s)
Amidohidrolasas/metabolismo , Encéfalo/enzimología , Piperidinas/síntesis química , Tomografía de Emisión de Positrones/métodos , Piridazinas/síntesis química , Animales , Encéfalo/diagnóstico por imagen , Técnicas de Química Sintética , Ligandos , Masculino , Piperidinas/química , Piperidinas/farmacocinética , Piridazinas/química , Piridazinas/farmacocinética , Radioquímica , RatasRESUMEN
The synthesis of NPTS, 6, a potent inhibitor of the type 1 glycine transporter (GlyT1) is described, as well as preparation of 6 in optically active and tritiated form for use as a radioligand for affinity displacement assay of GlyT1.