RESUMEN
As part of our efforts to identify a suitable back-up compound to our recently disclosed mGlu5 positive allosteric modulator (PAM) clinical candidate VU0490551/JNJ-46778212, this letter details the investigation and challenges of a novel series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one derivatives. From these efforts, compound 4k emerged as a potent and selective mGlu5 PAM displaying overall attractive in vitro (pharmacological and ADMET) and PK profiles combined with in vivo efficacy in preclinical models of schizophrenia. However, further advancement of the compound was precluded due to severely limiting CNS-related side-effects confirming the previously reported association between excessive mGlu5 activation and target-related toxicities.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Antipsicóticos/uso terapéutico , Pirazinas/uso terapéutico , Pirazoles/uso terapéutico , Receptor del Glutamato Metabotropico 5/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/química , Antipsicóticos/farmacocinética , Células HEK293 , Humanos , Masculino , Pirazinas/química , Pirazinas/farmacocinética , Pirazoles/química , Pirazoles/farmacocinética , Ratas Sprague-Dawley , Esquizofrenia/metabolismoRESUMEN
We report the discovery and SAR of two novel series of imidazopyrimidinones and dihydroimidazopyrimidinones as metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of several structural features in the western and eastern part of the imidazopyrimidinone core and combinations thereof, revealed compound 4a as a mGlu5 PAM with good in vitro potency and efficacy, acceptable drug metabolism and pharmacokinetic (DMPK) properties and in vivo efficacy in an amphetamine-based model of psychosis. However, the presence of CNS-mediated adverse effects in preclinical species precluded any further in vivo evaluation.
Asunto(s)
Antipsicóticos/química , Compuestos Heterocíclicos con 2 Anillos/química , Imidazoles/química , Pirimidinonas/química , Receptor del Glutamato Metabotropico 5/química , Regulación Alostérica , Animales , Antipsicóticos/síntesis química , Antipsicóticos/farmacocinética , Encéfalo/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Humanos , Imidazoles/síntesis química , Imidazoles/farmacocinética , Locomoción/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Unión Proteica , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Ratas , Receptor del Glutamato Metabotropico 5/metabolismo , Relación Estructura-ActividadRESUMEN
We report the continuation of a focused medicinal chemistry program aimed to further optimize a series of imidazo[1,2-a]pyrazines as a novel class of potent and selective phosphodiesterase 10A (PDE10A) inhibitors. In vitro and in vivo pharmacokinetic and pharmacodynamic evaluation allowed the selection of compound 25a for its assessment in preclinical models of psychosis. The evolution of our medicinal chemistry program, structure-activity relationship (SAR) analysis, as well as a detailed pharmacological profile for optimized lead 25a are described.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
We report the optimization of a series of novel metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) from a 5,6-bicyclic class of dihydropyrazolo[1,5-a]pyridin-4(5H)-ones containing a phenoxymethyl linker. Studies focused on a survey of non-amide containing hydrogen bond accepting (HBA) pharmacophore replacements. A highly potent and selective PAM, 2-(phenoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (11, VU0462054), bearing a simple ketone moiety, was identified (LE=0.52, LELP=3.2). In addition, hydroxyl, difluoro, ether, and amino variations were examined. Despite promising lead properties and exploration of alternative core heterocycles, linkers, and ketone replacements, oxidative metabolism and in vivo clearance remained problematic for the series.
Asunto(s)
Descubrimiento de Drogas , Piperidonas/farmacología , Pirazoles/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Ligandos , Estructura Molecular , Piperidonas/síntesis química , Piperidonas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-ActividadRESUMEN
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 PAMs containing an alkoxy-based linkage as an acetylene replacement. Exploration of several structural features including western pyridine ring isomers, positional amides, linker connectivity/position, and combinations thereof, reveal that these bicyclic modulators generally exhibit steep SAR and within specific subseries display a propensity for pharmacological mode switching at mGlu5 as well as antagonist activity at mGlu3. Structure-activity relationships within a dihydronaphthyridinone subseries uncovered 12c (VU0405372), a selective mGlu5 PAM with good in vitro potency, low glutamate fold-shift, acceptable DMPK properties, and in vivo efficacy in an amphetamine-based model of psychosis.
Asunto(s)
Naftiridinas/uso terapéutico , Receptor del Glutamato Metabotropico 5/efectos de los fármacos , Regulación Alostérica , Animales , Antipsicóticos/química , Células HEK293 , Humanos , Microsomas Hepáticos/metabolismo , Naftiridinas/síntesis química , Naftiridinas/química , Ratas , Receptor del Glutamato Metabotropico 5/agonistas , Esquizofrenia/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
We report the discovery of a series of imidazo[1,2-a]pyrazine derivatives as novel inhibitors of phosphodiesterase 10A (PDE10A). In a high-throughput screening campaign we identified the imidazopyrazine derivative 1, a PDE10A inhibitor with limited selectivity versus the other phosphodiesterases (PDEs). Subsequent investigation of 1 and replacement of the trimethoxyphenyl group by a (methoxyethyl)pyrazole moiety maintained PDE10A inhibition but enhanced selectivity against the other PDEs. Systematic examination and analysis of structure-activity and structure-property relationships resulted in the discovery of 2, an in vitro potent and selective inhibitor of PDE10A with high striatal occupancy of PDE10A, promising in vivo efficacy in different rodent behavioral models of schizophrenia, and a good pharmacokinetic profile in rats.
Asunto(s)
Inhibidores de Fosfodiesterasa/síntesis química , Hidrolasas Diéster Fosfóricas/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Administración Oral , Animales , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Inhibidores de Fosfodiesterasa/farmacología , Inhibidores de Fosfodiesterasa/uso terapéutico , Ratas , Relación Estructura-ActividadRESUMEN
[reaction: see text] A short synthesis of intermediates possessing the tricyclic core of natural madangamines, bioactive alkaloids found in marine sponges, is described. The key reaction entails the condensation of the sodium salt of diethylacetonedicarboxylate with a dihydropyridinium salt derivative. This new approach is modeled on a biogenetic proposal linking madangamines to ircinals, related alkaloids occurring in sponges of the same order.