RESUMEN
High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Pirimidinonas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Tiofenos/química , Administración Oral , Animales , Dolor Crónico/tratamiento farmacológico , Modelos Animales de Enfermedad , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Pirimidinonas/síntesis química , Pirimidinonas/uso terapéutico , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad , Tiofenos/síntesis química , Tiofenos/uso terapéuticoRESUMEN
Tricyclic sulfones were designed as gamma-secretase inhibitors and found to have excellent potency. Extensive SAR shows that a large number of sulfonamides at position 7 of the tricycle are very well tolerated. Compounds such as 15a and 15c showed remarkable in vivo potency.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Sulfonas/química , Sulfonas/farmacología , Administración Oral , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/sangre , Animales , Química Encefálica/efectos de los fármacos , Ratones , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonas/síntesis químicaRESUMEN
Complex tetracyclic sulfones were designed as gamma-secretase inhibitors and a stereoselective synthesis was achieved. Gamma-secretase activity was seen predominately in the (-) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Sulfonas/química , Péptidos beta-Amiloides/antagonistas & inhibidores , Animales , Diseño de Fármacos , Hepatocitos/metabolismo , Humanos , Ratones , Estereoisomerismo , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/farmacologíaRESUMEN
A-ring modifications on the triazafluorenone core structure were investigated. Five membered heterocycles such as pyrazoles and isothiazoles are not tolerated. It has been found that the pyrimidine nucleus was very well tolerated on the left hand side. Amino pyrimidine compounds 24 and 27 showed acceptable PK profile with significant brain penetration. Compound 9 served as a versatile intermediate for a number of chemical transformations.
Asunto(s)
Compuestos Aza/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Humanos , Estructura MolecularRESUMEN
A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.
Asunto(s)
Benzazepinas/química , Antagonistas de Dopamina/química , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Masculino , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/fisiologíaRESUMEN
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Asunto(s)
Benzazepinas/química , Benzazepinas/farmacología , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Ratas , Receptores de Dopamina D1/fisiologíaRESUMEN
Introduction of small unsaturated alkylamino groups at the 4-position of the A-ring of the tricyclic framework (triazafluorenone) afforded extremely potent and selective mGluR1 antagonists with desirable properties. Compounds 11q and 11s are active in the SNL pain model with ED(50)s 3.3 and 6.4 mg/kg respectively. Metabolic outcome of propargyl amino moiety was studied.
Asunto(s)
Neuralgia/tratamiento farmacológico , Piridinas/química , Pirimidinas/química , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Piridinas/farmacología , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel aminobenzimidazoles was prepared and evaluated for h-MCH-R1 antagonist properties. Most of the compounds showed excellent h-MCH-R1 binding affinity as well as mouse ex vivo binding. Compounds 9 and 18 were active in mouse DIO studies at 30mpk.
Asunto(s)
Fármacos Antiobesidad/farmacología , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Receptores de Somatostatina/antagonistas & inhibidores , Animales , Fármacos Antiobesidad/química , Bencimidazoles/química , Unión Competitiva/efectos de los fármacos , Dieta , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Ratones , Ratones Obesos , Conformación Molecular , Obesidad/tratamiento farmacológico , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Acylated and aroylated hydrazinoclozapines are highly potent dopamine D(1) antagonists that show remarkable selectivity over other dopamine receptors. The most potent compound in this series is the 2,6-dimethoxybenzhydrazide 33 with a D(1)K(i) of 1.6 nM and 212-fold selectivity over D(2) receptor.
Asunto(s)
Clozapina/química , Clozapina/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Hidrazinas/química , Receptores de Dopamina D1/antagonistas & inhibidores , Clozapina/síntesis química , Clozapina/clasificación , Antagonistas de Dopamina/química , Antagonistas de Dopamina/clasificación , Antagonistas de los Receptores de Dopamina D2 , Estructura Molecular , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of potent and selective inhibitors of h-MCH-R1 has been developed based on the piperidine glycineamide compounds I and II. These structurally more rigid tetrahydroisoquinolines (III and IV) showed better pharmacokinetics. The highly potent compounds 12d and 12g displayed excellent rat pk.