RESUMEN
Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism.
Asunto(s)
Descubrimiento de Drogas , Pirimidinas/farmacología , Quinolinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Pirimidinas/química , Quinolinas/química , Ratas , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we describe the continued optimization of M4 positive allosteric modulators (PAMs) within the 5-amino-thieno[2,3-c]pyridazine series of compounds. In this letter, we disclose our studies on tertiary amides derived from substituted azetidines. This series provided excellent CNS penetration, which had been challenging to consistently achieve in other amide series. Efforts to mitigate high clearance, aided by metabolic softspot analysis, were unsuccessful and precluded this series from further consideration as a preclinical candidate. In the course of this study, we found that potassium tetrafluoroborate salts could be engaged in a tosyl hydrazone reductive cross coupling reaction, a previously unreported transformation, which expands the synthetic utility of the methodology.
Asunto(s)
Amidas/química , Azetidinas/química , Receptor Muscarínico M4/metabolismo , Regulación Alostérica , Amidas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , Unión Proteica , Piridazinas/síntesis química , Piridazinas/química , Piridazinas/metabolismo , Receptor Muscarínico M4/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu5 NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu5 NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu5 versus DAT.
Asunto(s)
Amidas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica , Amidas/farmacocinética , Amidas/farmacología , Animales , Permeabilidad de la Membrana Celular/efectos de los fármacos , Perros , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Células de Riñón Canino Madin Darby , Ratones , Microsomas Hepáticos/metabolismo , Piridinas/química , Ratas , Receptor del Glutamato Metabotropico 5/química , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
This letter details the continued chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M4 PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described. This work culminated in the discovery of VU6000918, which demonstrated robust efficacy in a rat amphetamine-induced hyperlocomotion reversal model at a minimum efficacious dose of 0.3mg/kg.
Asunto(s)
Amidas/farmacología , Azetidinas/farmacología , Receptor Muscarínico M4/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Animales , Azetidinas/síntesis química , Azetidinas/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Preclinical evidence in support of the potential utility of mGlu5 NAMs for the treatment of a variety of psychiatric and neurodegenerative disorders is extensive, and multiple such molecules have entered clinical trials. Despite some promising results from clinical studies, no small molecule mGlu5 NAM has yet to reach market. Here we present the discovery and evaluation of N-(5-fluoropyridin-2-yl)-6-methyl-4-(pyrimidin-5-yloxy)picolinamide (27, VU0424238), a compound selected for clinical evaluation. Compound 27 is more than 900-fold selective for mGlu5 versus the other mGlu receptors, and binding studies established a Ki value of 4.4 nM at a known allosteric binding site. Compound 27 had a clearance of 19.3 and 15.5 mL/min/kg in rats and cynomolgus monkeys, respectively. Imaging studies using a known mGlu5 PET ligand demonstrated 50% receptor occupancy at an oral dose of 0.8 mg/kg in rats and an intravenous dose of 0.06 mg/kg in baboons.
Asunto(s)
Aminopiridinas/farmacología , Evaluación Preclínica de Medicamentos/métodos , Ácidos Picolínicos/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-Actividad , Regulación Alostérica , Aminopiridinas/síntesis química , Animales , Técnicas de Química Sintética , Células HEK293 , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos , Ácidos Picolínicos/síntesis química , Ratas Sprague-Dawley , Receptor del Glutamato Metabotropico 5/agonistas , Distribución TisularRESUMEN
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson's disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties.
Asunto(s)
Descubrimiento de Drogas , Piridazinas/farmacología , Tiofenos/farmacología , Investigación Biomédica Traslacional , Regulación Alostérica , Animales , Cristalografía por Rayos X , Enlace de Hidrógeno , Piridazinas/química , Ratas , Relación Estructura-Actividad , Tiofenos/químicaRESUMEN
Selective negative allosteric modulators (NAMs) of each of the group I metabotropic glutamate receptors (mGlu1 and mGlu5) have been well characterized in the literature and offer potential as therapeutics in several disorders of the central nervous system (CNS). Still, compounds that are potent mGlu1/5 NAMs with selectivity versus the other six members of the mGlu family as well as the balance of properties required for use in vivo are lacking. A medicinal chemistry effort centered on the identification of a lead series with the potential of delivering such compounds is described in this Letter. Specifically, a new class of pyrido[1',2':1,5]pyrazolo[4,3-d]pyrimidin-4-amines was designed as a novel isosteric replacement for 4-aminoquinazolines, and compounds from within this chemotype exhibited dual NAM activity at both group I mGlus. One compound, VU0467558 (29), demonstrated near equipotent activity at both receptors, selectivity versus other mGlus, a favorable ancillary pharmacology profile, and CNS exposure in rodents.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Sistema Nervioso Central/efectos de los fármacos , Pirazoles/farmacología , Pirimidinas/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Marketed drugs cleared by aldehyde oxidase (AO) are few, with no known clinically relevant pharmacokinetic drug interactions associated with AO inhibition, whereas cytochrome P450 (P450) inhibition or induction mediates a number of clinical drug interactions. Little attention has been given to the consequences of coadministering a P450 inhibitor with a compound metabolized by both AO and P450. Upon discovering that VU0409106 (1) was metabolized by AO (to M1) and P450 enzymes (to M4-M6), we sought to evaluate the in vivo disposition of 1 and its metabolites in rats with attenuated P450 activity. Male rats were orally pretreated with the pan-P450 inactivator, 1-aminobenzotriazole (ABT), before an i.p. dose of 1. Interestingly, the plasma area under the curve (AUC) of M1 was increased 15-fold in ABT-treated rats, indicating a metabolic shunt toward AO resulted from the drug interaction condition. The AUC of 1 also increased 7.8-fold. Accordingly, plasma clearance of 1 decreased from 53.5 to 15.3 ml/min per kilogram in ABT-pretreated rats receiving an i.v. dose of 1. Consistent with these data, M1 formation in hepatic S9 increased with NADPH-exclusion to eliminate P450 activity (50% over reactions containing NADPH). These studies reflect possible consequences of a drug interaction between P450 inhibitors and compounds cleared by both AO and P450 enzymes. Notably, increased exposure to an AO metabolite may hold clinical relevance for active metabolites or those mediating toxicity at elevated concentrations. The recent rise in clinical drug candidates metabolized by AO underscores the importance of these findings and the need for clinical studies to fully understand these risks.
Asunto(s)
Aldehído Oxidasa/metabolismo , Benzamidas/farmacocinética , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Tiazoles/farmacocinética , Triazoles/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Benzamidas/administración & dosificación , Benzamidas/metabolismo , Biotransformación , Inhibidores Enzimáticos del Citocromo P-450/administración & dosificación , Interacciones Farmacológicas , Humanos , Masculino , Tasa de Depuración Metabólica , Microsomas Hepáticos/enzimología , Ratas Sprague-Dawley , Medición de Riesgo , Especificidad por Sustrato , Tiazoles/administración & dosificación , Tiazoles/metabolismo , Triazoles/administración & dosificaciónRESUMEN
Cocaine abuse remains a public health concern for which pharmacotherapies are largely ineffective. Comorbidities between cocaine abuse, depression, and anxiety support the development of novel treatments targeting multiple symptom clusters. Selective negative allosteric modulators (NAMs) targeting the metabotropic glutamate receptor 5 (mGlu5) subtype are currently in clinical trials for the treatment of multiple neuropsychiatric disorders and have shown promise in preclinical models of substance abuse. However, complete blockade or inverse agonist activity by some full mGlu5 NAM chemotypes demonstrated adverse effects, including psychosis in humans and psychotomimetic-like effects in animals, suggesting a narrow therapeutic window. Development of partial mGlu5 NAMs, characterized by their submaximal but saturable levels of blockade, may represent a novel approach to broaden the therapeutic window. To understand potential therapeutic vs adverse effects in preclinical behavioral assays, we examined the partial mGlu5 NAMs, M-5MPEP and Br-5MPEPy, in comparison with the full mGlu5 NAM MTEP across models of addiction and psychotomimetic-like activity. M-5MPEP, Br-5MPEPy, and MTEP dose-dependently decreased cocaine self-administration and attenuated the discriminative stimulus effects of cocaine. M-5MPEP and Br-5MPEPy also demonstrated antidepressant- and anxiolytic-like activity. Dose-dependent effects of partial and full mGlu5 NAMs in these assays corresponded with increasing in vivo mGlu5 occupancy, demonstrating an orderly occupancy-to-efficacy relationship. PCP-induced hyperlocomotion was potentiated by MTEP, but not by M-5MPEP and Br-5MPEPy. Further, MTEP, but not M-5MPEP, potentiated the discriminative-stimulus effects of PCP. The present data suggest that partial mGlu5 NAM activity is sufficient to produce therapeutic effects similar to full mGlu5 NAMs, but with a broader therapeutic index.
Asunto(s)
Alquinos/administración & dosificación , Alquinos/farmacología , Alquinos/farmacocinética , Encéfalo/efectos de los fármacos , Cocaína/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/farmacología , Piridinas/farmacocinética , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Animales , Ansiolíticos/administración & dosificación , Antidepresivos/administración & dosificación , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Fenciclidina/administración & dosificación , Ratas Sprague-Dawley , Autoadministración , Tiazoles/administración & dosificación , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Both orthosteric and allosteric antagonists of the group II metabotropic glutamate receptors (mGlus) have been used to establish a link between mGlu2/3 inhibition and a variety of CNS diseases and disorders. Though these tools typically have good selectivity for mGlu2/3 versus the remaining six members of the mGlu family, compounds that are selective for only one of the individual group II mGlus have proved elusive. Herein we report on the discovery of a potent and highly selective mGlu2 negative allosteric modulator 58 (VU6001192) from a series of 4-oxo-1-aryl-1,4-dihydroquinoline-3-carboxamides. The concept for the design of this series centered on morphing a quinoline series recently disclosed in the patent literature into a chemotype previously used for the preparation of muscarinic acetylcholine receptor subtype 1 positive allosteric modulators. Compound 58 exhibits a favorable profile and will be a useful tool for understanding the biological implications of selective inhibition of mGlu2 in the CNS.
Asunto(s)
Quinolonas/síntesis química , Quinolonas/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Animales , Sistema Nervioso Central/efectos de los fármacos , Descubrimiento de Drogas , Ratones , Unión Proteica , Quinolinas/síntesis química , Quinolinas/farmacología , Quinolonas/farmacocinética , Ratas , Receptor Muscarínico M1/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
The therapeutic potential of selective mGlu1 activation is vastly unexplored relative to the other group I mGlu receptor, mGlu5; therefore, our lab has focused considerable effort toward developing mGlu1 positive allosteric modulators (PAMs) suitable as in vivo proof of concept tool compounds. Optimization of a series of mGlu1 PAMs based on an N-(3-chloro-4-(1,3-dioxoisoindolin-2-yl)phenyl)-3-methylfuran-2-carboxamide scaffold provided 17e, a potent (mGlu1 EC50 = 31.8 nM) and highly CNS penetrant (brain to plasma ratio (Kp) of 1.02) mGlu1 PAM tool compound, that potentiated not only wild-type human mGlu1 but also mutant mGlu1 receptors derived from deleterious GRM1 mutations found in schizophrenic patients. Moreover, both electrophysiological and in vivo studies indicate the mGlu1 ago-PAMs/PAMs do not possess the same epileptiform adverse effect liability as mGlu5 ago-PAMs/PAMs and maintain temporal activity suggesting a broader therapeutic window.
Asunto(s)
Sistema Nervioso Central/metabolismo , Moduladores del GABA/síntesis química , Moduladores del GABA/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Esquizofrenia/genética , Animales , Epilepsia/inducido químicamente , Agonistas del GABA/efectos adversos , Agonistas del GABA/farmacocinética , Agonistas del GABA/uso terapéutico , Moduladores del GABA/farmacocinética , Semivida , Humanos , Conformación Molecular , Ratas , Receptor del Glutamato Metabotropico 5/agonistas , Receptores de Glutamato Metabotrópico/genética , Relación Estructura-ActividadRESUMEN
Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.
Asunto(s)
Ansiolíticos/química , Antidepresivos/química , Encéfalo/metabolismo , Compuestos Heterocíclicos con 2 Anillos/química , Piridinas/química , Receptores de Glutamato Metabotrópico/metabolismo , Regulación Alostérica , Animales , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Calcio/metabolismo , Perros , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Células de Riñón Canino Madin Darby , Ratones , Microsomas Hepáticos/metabolismo , Permeabilidad , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Once thought to be an artifact of microsomal systems, atypical kinetics with cytochrome P450 (CYP) enzymes have been extensively investigated in vitro and found to be substrate and species dependent. Building upon increasing reports of heterotropic CYP activation and inhibition in clinical settings, we screened a compound library of clinically approved drugs and various probe compounds to identify the frequency of heterotropism observed with different drug classes and the associated CYP enzymes thereof (1A2, 2C9, 2D6, and 3A4/5). Results of this screen revealed that the prescribed androgen receptor antagonist flutamide activated the intrinsic midazolam hydroxylase activity of CYP3A in human hepatic microsomes (66%), rat and human hepatocytes (36 and 160%, respectively), and in vivo in male Sprague-Dawley rats (>2-fold, combined area under the curve of primary rat in vivo midazolam metabolites). In addition, a screen of the pharmacologically active metabolite 2-hydroxy-flutamide revealed that this principle metabolite increased CYP3A metabolism of midazolam in human microsomes (30%) and hepatocytes (110%). Importantly, both flutamide and 2-hydroxy-flutamide demonstrated a pronounced increase in the CYP3A-mediated metabolism of commonly paired medications, nifedipine (antihypertensive) and amiodarone (antiarrhythmic), in multispecies hepatocytes (100% over baseline). These data serve to highlight the importance of an appropriate substrate and in vitro system selection in the pharmacokinetic modeling of atypical enzyme kinetics. In addition, the results of our investigation have illuminated a previously undiscovered class of heterotropic CYP3A activators and have demonstrated the importance of selecting commonly paired therapeutics in the in vitro and in vivo modeling of projected clinical outcomes.
Asunto(s)
Antagonistas de Receptores Androgénicos/metabolismo , Citocromo P-450 CYP3A/metabolismo , Activadores de Enzimas/metabolismo , Flutamida/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Animales , Evaluación Preclínica de Medicamentos/métodos , Activadores de Enzimas/farmacología , Femenino , Flutamida/farmacología , Cobayas , Humanos , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Ratas , Ratas Sprague-Dawley , Porcinos , Porcinos EnanosRESUMEN
This Letter describes the continued optimization of the MLPCN probe ML375, a highly selective M5 negative allosteric modulator (NAM), through a combination of matrix libraries and iterative parallel synthesis. True to certain allosteric ligands, SAR was shallow, and the matrix library approach highlighted the challenges with M5 NAM SAR within in this chemotype. Once again, enantiospecific activity was noted, and potency at rat and human M5 were improved over ML375, along with slight enhancement in physiochemical properties, certain in vitro DMPK parameters and CNS distribution. Attempts to further enhance pharmacokinetics with deuterium incorporation afforded mixed results, but pretreatment with a pan-P450 inhibitor (1-aminobenzotriazole; ABT) provided increased plasma exposure.
Asunto(s)
Imidazoles/química , Indoles/química , Receptor Muscarínico M5/química , Regulación Alostérica , Animales , Encéfalo/metabolismo , Semivida , Humanos , Imidazoles/metabolismo , Imidazoles/farmacocinética , Indoles/metabolismo , Indoles/farmacocinética , Microsomas Hepáticos/metabolismo , Unión Proteica , Ratas , Receptor Muscarínico M5/genética , Receptor Muscarínico M5/metabolismo , Relación Estructura-ActividadRESUMEN
Approaches to efficiently and accurately define the pharmacokinetics (PK) of large sets of small molecules in rodents have been previously described. Likewise, a variety of methods for determining brain tissue distribution (BTD) have been reported for use in the discovery of therapeutics targeting the central nervous system (CNS). Herein we describe a novel cassette approach to efficiently obtain concurrent PK and BTD data from a dose of up to five compounds in one rat over 24 h. In conjunction with fraction unbound (fu) data obtained in plasma and brain homogenate, this approach serves as an efficient means to determine compound unbound brain:unbound plasma partition coefficients (K p,uu), thereby providing insight to compounds bearing poor permeability and/or active transporter activity impacting their permeation of the blood-brain barrier (BBB). This integrated approach was utilized in a lead optimization effort towards the discovery of CNS-penetrant allosteric modulators of a seven-transmembrane (7TM) receptor target. Rat PK and brain distribution was rapidly obtained for 70 compounds and correlated to data obtained from in vitro assessments. Two compounds that were evaluated in cassette and discrete studies, displayed agreement in PK (compound 1: cassette CLp = 1.6 mL min(-1) kg(-1), discrete CLp = 1.6 mL min(-1) kg(-1); compound 2: cassette CLp = 11 mL min(-1) kg(-1), discrete CLp = 8.1 mL min(-1) kg(-1)) and BTD (compound 1: cassette K p = 0.11, discrete K p = 0.09; compound 2: cassette K p < 0.05, discrete K p = 0.04). The resulting data were used to guide medicinal chemistry efforts and to enable the progression of optimized compounds to in vivo pharmacodynamic assessments.
RESUMEN
Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
Asunto(s)
Aprendizaje por Asociación/efectos de los fármacos , Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Psicotrópicos/farmacología , Piridazinas/farmacología , Receptor Muscarínico M4/metabolismo , Tiofenos/farmacología , Anfetaminas/toxicidad , Animales , Aprendizaje por Asociación/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Línea Celular , Estimulantes del Sistema Nervioso Central/toxicidad , Colinérgicos/síntesis química , Colinérgicos/farmacocinética , Colinérgicos/farmacología , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Psicotrópicos/síntesis química , Psicotrópicos/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Tiofenos/síntesis química , Tiofenos/farmacocinéticaRESUMEN
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of pyrazine analog VU0431316 is described in this Letter. VU0431316 is a potent and selective non-competitive antagonist of mGlu5 that binds at a known allosteric binding site. VU0431316 demonstrates an attractive DMPK profile, including moderate clearance and good bioavailability in rats. Intraperitoneal (IP) dosing of VU0431316 in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists and other anxiolytics, produced dose proportional effects.
Asunto(s)
Ansiedad/tratamiento farmacológico , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Ácidos Picolínicos/farmacología , Pirazinas/farmacología , Receptor del Glutamato Metabotropico 5/antagonistas & inhibidores , Sitio Alostérico/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Estructura Molecular , Ácidos Picolínicos/administración & dosificación , Ácidos Picolínicos/química , Pirazinas/administración & dosificación , Pirazinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Of the five G-protein-coupled muscarinic acetylcholine receptors (mAChRs; M1-M5), M5 is the least explored and understood due to a lack of mAChR subtype-selective ligands. We recently performed a high-throughput functional screen and identified a number of weak antagonist hits that are selective for the M5 receptor. Here, we report an iterative parallel synthesis and detailed molecular pharmacologic profiling effort that led to the discovery of the first highly selective, central nervous system (CNS)-penetrant M5-orthosteric antagonist, with sub-micromolar potency (hM5 IC50=450â nM, hM5 Ki=340â nM, M1-M4 IC50>30â µM), enantiospecific inhibition, and an acceptable drug metabolism and pharmacokinetics (DMPK) profile for in vitro and electrophysiology studies. This compound will be a powerful tool and molecular probe for the further investigation into the role of M5 in addiction and other diseases.
Asunto(s)
Acetofenonas/química , Isoxazoles/química , Sondas Moleculares/química , Antagonistas Muscarínicos/química , Receptor Muscarínico M5/antagonistas & inhibidores , Acetofenonas/metabolismo , Acetofenonas/farmacocinética , Animales , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Isoxazoles/metabolismo , Isoxazoles/farmacocinética , Sondas Moleculares/metabolismo , Sondas Moleculares/farmacocinética , Antagonistas Muscarínicos/metabolismo , Antagonistas Muscarínicos/farmacocinética , Unión Proteica , Ratas , Receptor Muscarínico M5/metabolismoRESUMEN
Development of SAR in an aryl ether series of mGlu5 NAMs leading to the identification of tool compound VU0409106 is described in this Letter. VU0409106 is a potent and selective negative allosteric modulator of mGlu5 that binds at the known allosteric binding site and demonstrates good CNS exposure following intraperitoneal dosing in mice. VU0409106 also proved efficacious in a mouse marble burying model of anxiety, an assay known to be sensitive to mGlu5 antagonists as well as clinically efficacious anxiolytics.