RESUMEN
The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.
RESUMEN
Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.
Asunto(s)
Indazoles/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Tetrazoles/farmacología , Animales , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Ratones , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-Actividad , Tetrazoles/síntesis química , Tetrazoles/farmacocinéticaAsunto(s)
Estimulantes del Apetito/química , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ghrelina/antagonistas & inhibidores , Hidrazinas/química , Hidrazinas/farmacología , Receptores de Ghrelina , Animales , Estimulantes del Apetito/farmacocinética , Estimulantes del Apetito/farmacología , Dicroismo Circular , Femenino , Ghrelina/metabolismo , Hidrazinas/farmacocinética , Ligandos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptores de Ghrelina/antagonistas & inhibidores , Relación Estructura-ActividadRESUMEN
A novel growth hormone secretagogues type 1a (GHS1a) receptors antagonist (2R)-N'-[3,5- bis(trifluoromethyl)phenyl]-2-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(3- pyridinyl)ethanohydrazide (GSK1614343) was functionally characterised in rat pituitary adenoma cell line, RC-4B/C endogenously expressing GHS1a receptors. The antagonism profile of GSK1614343 was compared with that of 6-[(4-fluorophenyl)oxy]-2-methyl-3-{[(3S)-1-(1-methylethyl)-3- piperidinyl]methyl}-4(3H)-quinazolinone (YIL-781) another ghrelin receptor antagonist recently published. The activity of both compounds was also evaluated at rat recombinant GHS1a receptors. The characterization of the two antagonists was performed by intracellular calcium mobilization measurements by using fluorometric imaging plate reader (FLIPR) technology and inositol phosphate (IP) turnover measurements by [3H]-IP accumulation assay. RC-4B/C and U2-OS cells transiently transduced with rat GHS1a receptors virus were used. In RC-4B/C cells, GSK1614343 and YIL-781, depressed the ghrelin maximal response in FLIPR assay as result of hemi-equilibria phenomenon. When using the [3H]-IP accumulation assay both compounds behaved as competitive antagonist with pKB values of 8.03 for GSK1614343 and 7.54 for YIL-781. In rat recombinant receptor, GSK1614343 and YIL-781 inhibited the calcium response induced by ghrelin with pIC50 values of 7.90 and 8.27, respectively. GSK1614343 and YIL-781 did not show intrinsic activity in both endogenously expressed and recombinant rat GHS1a receptors. The new ghrelin receptor antagonist GSK1614343 is a potent competitive antagonist in rat pituitary RC-4B/C cells endogenously expressing GHS1a receptors when equilibrium conditions between ligand and receptor are reached in the test assay. GSK1614343 represents a useful tool to investigate the physiological relevance of the ghrelin system in rat models.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Regulación de la Expresión Génica , Hidrazinas/farmacología , Pirroles/farmacología , Receptores de Ghrelina/antagonistas & inhibidores , Receptores de Ghrelina/genética , Secuencia de Aminoácidos , Animales , Baculoviridae/genética , Calcio/metabolismo , Línea Celular Tumoral , Humanos , Fosfatos de Inositol/metabolismo , Datos de Secuencia Molecular , Regiones Promotoras Genéticas/genética , RatasRESUMEN
A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Diseño de Fármacos , Ingestión de Alimentos/efectos de los fármacos , Receptores de Neuropéptido Y/antagonistas & inhibidores , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Relación Estructura-ActividadAsunto(s)
Hidrazinas/química , Receptores de Ghrelina/antagonistas & inhibidores , Línea Celular , Evaluación Preclínica de Medicamentos , Trastornos de Alimentación y de la Ingestión de Alimentos/tratamiento farmacológico , Humanos , Hidrazinas/síntesis química , Hidrazinas/uso terapéutico , Receptores de Ghrelina/metabolismo , Relación Estructura-ActividadAsunto(s)
Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Diseño de Fármacos , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Animales , Ansiedad/patología , Hormona Liberadora de Corticotropina/metabolismo , Depresión/patología , Modelos Químicos , Pirazoles/síntesis química , Pirazoles/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Corticotropin-releasing factor (CRF), a 41 amino acid peptide neurohormone synthesised by specific hypothalamic nuclei in the brain, is implicated in stress-related function. Antagonism of CRF(1) receptors is an attractive therapeutic approach for the treatment of depression and anxiety. Unsaturated tetrahydrotriazaacenaphthylenes of general structure 3 have been identified as potent and selective CRF(1) receptor antagonists with a suitable oral pharmacokinetic profile.
Asunto(s)
Naftalenos/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Humanos , Naftalenos/administración & dosificación , Naftalenos/química , Naftalenos/farmacocinética , Proteínas Recombinantes/antagonistas & inhibidoresRESUMEN
Exploiting the SAR of the known pyrrole derivatives, a new class of mGluR1 antagonists was developed through a cyclization of the C-2 position on the pyrrole N-1 nitrogen. The resulting pyrrolo[1,2-a]pyrazinones are potent and noncompetitive antagonists.
Asunto(s)
Pirazinas/química , Pirazinas/farmacología , Pirroles/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Células CHO , Cricetinae , Concentración 50 Inhibidora , Estructura Molecular , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.
Asunto(s)
Ésteres/síntesis química , Ésteres/farmacología , Pirroles/síntesis química , Pirroles/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Azidas/síntesis química , Azidas/farmacocinética , Fenómenos Químicos , Química Física , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Ácidos Hidroxámicos/síntesis química , Ácidos Hidroxámicos/farmacocinética , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratones , Conformación Molecular , Ratas , Solubilidad , Espectrofotometría Infrarroja , Relación Estructura-ActividadRESUMEN
Following the disclosure of 3-(1,2,2-trimethylpropyl) 4-[3,5-dimethyl-2-propyloxycarbonyl]pyrrolecarboxylate as a potent and selective mGluR1 non-competitive antagonist, the role and the importance of the pyrrole template were investigated. Different aromatic moieties were investigated as possible bio-isosteric replacement of the original scaffold and some of them were shown to be partially able to mimic the properties of the original pyrrole ring.
Asunto(s)
Analgésicos no Narcóticos/síntesis química , Pirroles/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos no Narcóticos/farmacología , Animales , Derivados del Benceno/química , Derivados del Benceno/farmacología , Unión Competitiva/efectos de los fármacos , Células CHO , Cricetinae , Ésteres/síntesis química , Ésteres/farmacología , Concentración 50 Inhibidora , Ratones , Nociceptores/efectos de los fármacos , Dimensión del Dolor , Pirroles/farmacología , Ratas , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/genética , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacologíaRESUMEN
Following the disclosure of 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester [3,5-dimethyl PPP] as a potent and selective mGluR1 non-competitive antagonist, we report here further in vivo characterization of this important tool and disclose the investigation of the C-5 position, which led to very potent compounds.
Asunto(s)
Ésteres/síntesis química , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Pirroles/síntesis química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Animales , Unión Competitiva/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrofisiología , Ésteres/farmacología , Indicadores y Reactivos , Morfina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Nociceptores/efectos de los fármacos , Pirroles/farmacología , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Relación Estructura-Actividad , Transmisión Sináptica/efectos de los fármacos , Tálamo/efectos de los fármacos , Tálamo/metabolismoRESUMEN
Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.