RESUMEN
In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer's disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 µM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Quinolonas/farmacología , Acetilcolinesterasa/metabolismo , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Simulación del Acoplamiento Molecular , Monoaminooxidasa/metabolismo , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
The multifactorial nature of Alzheimer's disease necessitates the development of agents able to interfere with different relevant targets. A series of 22 tailored chromanones was conceptualized, synthesized, and subjected to biological evaluation. We identified one representative bearing a linker-connected azepane moiety (compound 19) with balanced pharmacological properties. Compound 19 exhibited inhibitory activities against human acetyl-, butyrylcholinesterase and monoamine oxidase-B, as well as high affinity to both the σ1 and σ2 receptors. Our study provides a framework for the development of further chromanone-based multineurotarget agents.
RESUMEN
The complex nature of multifactorial diseases, such as Morbus Alzheimer, has produced a strong need to design multitarget-directed ligands to address the involved complementary pathways. We performed a purposive structural modification of a tetratarget small-molecule, that is contilisant, and generated a combinatorial library of 28 substituted chromen-4-ones. The compounds comprise a basic moiety which is linker-connected to the 6-position of the heterocyclic chromenone core. The syntheses were accomplished by Mitsunobu- or Williamson-type ether formations. The resulting library members were evaluated at a panel of seven human enzymes, all of which being involved in the pathophysiology of neurodegeneration. A concomitant inhibition of human acetylcholinesterase and human monoamine oxidase B, with IC50 values of 5.58 and 7.20 µM, respectively, was achieved with the dual-target 6-(4-(piperidin-1-yl)butoxy)-4H-chromen-4-one (7).
RESUMEN
Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.
Asunto(s)
Isoquinolinas/farmacología , Receptores de Dopamina D1/agonistas , Acetilcolina/metabolismo , Administración Oral , Regulación Alostérica/efectos de los fármacos , Animales , Sitios de Unión , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Células HEK293 , Semivida , Humanos , Isoquinolinas/química , Isoquinolinas/farmacocinética , Riñón/efectos de los fármacos , Riñón/metabolismo , Locomoción/efectos de los fármacos , Ratones , Conformación Molecular , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Ratas , Receptores de Dopamina D1/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4ß-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.
Asunto(s)
Compuestos Bicíclicos con Puentes/farmacología , Receptores de Glutamato Metabotrópico/agonistas , Compuestos de Espiro/farmacología , Animales , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/metabolismo , Cristalografía por Rayos X , Humanos , Masculino , Modelos Moleculares , Estructura Terciaria de Proteína , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Compuestos de Espiro/química , Compuestos de Espiro/metabolismoRESUMEN
Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Receptores de Glutamato Metabotrópico/agonistas , Triazoles/química , Regulación Alostérica , Animales , Unión Competitiva , Compuestos Bicíclicos con Puentes/farmacocinética , Compuestos Bicíclicos con Puentes/farmacología , Calcio/metabolismo , AMP Cíclico/metabolismo , Perros , Agonismo Parcial de Drogas , Humanos , Masculino , Ratones , Modelos Moleculares , Actividad Motora/efectos de los fármacos , Mutagénesis Sitio-Dirigida , Estructura Terciaria de Proteína , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Estereoisomerismo , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A flexible approach to functionalized and enantioenriched aziridines has been developed from an intermediate aziridinylmethyl tosylate. This protocol features a Cu-catalyzed Grignard substitution reaction that allows a range of functionalized organic fragments to be incorporated. Moreover, a convenient one-pot procedure is outlined that allows the trityl group to be exchanged for a range of common N-protecting groups.
Asunto(s)
Aziridinas/síntesis química , Alquilación , Aziridinas/química , Cobre/química , Estructura Molecular , EstereoisomerismoRESUMEN
A novel series of 1-aryl-3,4-dihydro-1H-quinolin-2-ones have been discovered as potent and selective norepinephrine reuptake inhibitors. Efficient synthetic routes have been developed which allow for the multi-gram preparation of both final targets and advanced intermediates for SAR expansion.