RESUMEN
A series of novel AMPA receptor positive modulators displaying CNS penetration have been discovered with sub-micromolar activity and good selectivity over the cardiac channel receptor, hERG. We describe here the synthesis of these compounds which are biaryl pyrrolidine and tetrahydrofuran sulfonamides and disclose their activities against the human GluA2 flip isoform homotetrameric receptor.
Asunto(s)
Furanos/farmacología , Pirrolidinas/farmacología , Receptores AMPA/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/efectos de los fármacos , Furanos/química , Humanos , Isoformas de Proteínas , Pirrolidinas/química , Pirrolidinas/farmacocinética , Relación Estructura-Actividad , SulfonamidasRESUMEN
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different in vitro pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Asunto(s)
Quinolinas/farmacología , Receptores de Serotonina 5-HT1/efectos de los fármacos , Administración Oral , Animales , Disponibilidad Biológica , Ligandos , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Asunto(s)
Piperazinas/síntesis química , Quinolinas/síntesis química , Antagonistas del Receptor de Serotonina 5-HT1 , Animales , Barrera Hematoencefálica/metabolismo , Corteza Cerebral/metabolismo , Humanos , Técnicas In Vitro , Piperazinas/farmacocinética , Piperazinas/farmacología , Quinolinas/farmacocinética , Quinolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Proteínas Recombinantes/farmacología , Relación Estructura-ActividadRESUMEN
At their clinical doses, current antipsychotic agents share the property of both dopamine D(2) and D(3) receptor blockade. However, a major disadvantage of many current medications are the observed extrapyramidal side-effects (EPS), postulated to arise from D(2) receptor antagonism. Consequently, a selective dopamine D(3) receptor antagonist could offer an attractive antipsychotic therapy, devoid of the unwanted EPS. Using SAR information gained in two previously reported series of potent and selective D(3) receptor antagonists, as exemplified by the 2,3,4,5-tetrahydro-1H-3-benzazepine 10 and the 2,3-dihydro-1H-isoindoline 11, a range of 7-sulfonyloxy- and 7-sulfonylbenzazepines has been prepared. Compounds of this type combined a high level of D(3) affinity and selectivity vs D(2) with an excellent pharmacokinetic profile in the rat. Subsequent optimization of this series to improve selectivity over a range of receptors and reduce cytochrome P450 inhibitory potential gave trans-3-(2-(4-((3-(3-(5-methyl-1,2,4-oxidiazolyl))phenyl)carboxamido)cyclohexyl)ethyl)-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (58, SB-414796). This compound is a potent and selective dopamine D(3) receptor antagonist with high oral bioavailability and is CNS penetrant in the rat. Subsequent evaluation in the rat has shown that 58 preferentially reduces firing of dopaminergic cells in the ventral tegmental area (A10) compared to the substantia nigra (A9), an observation consistent with a prediction for atypical antipsychotic efficacy. In a separate study, 58 has been shown to block expression of the conditioned place preference (CPP) response to cocaine in male rats, suggesting that it may also have a role in the treatment of cue-induced relapse in drug-free cocaine addicts.
Asunto(s)
Antipsicóticos/síntesis química , Benzazepinas/síntesis química , Antagonistas de Dopamina/síntesis química , Antagonistas de los Receptores de Dopamina D2 , Sulfonas/síntesis química , Potenciales de Acción/efectos de los fármacos , Administración Oral , Animales , Antipsicóticos/farmacocinética , Antipsicóticos/farmacología , Benzazepinas/farmacocinética , Benzazepinas/farmacología , Disponibilidad Biológica , Células CHO , Catalepsia/inducido químicamente , Cocaína/farmacología , Condicionamiento Clásico/efectos de los fármacos , Cricetinae , Dopamina/metabolismo , Antagonistas de Dopamina/farmacocinética , Antagonistas de Dopamina/farmacología , Diseño de Fármacos , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/fisiología , Prolactina/sangre , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D3 , Relación Estructura-Actividad , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/fisiología , Sulfonas/farmacocinética , Sulfonas/farmacología , Área Tegmental Ventral/citología , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/fisiologíaRESUMEN
A novel series of AMPAR positive modulators is described that were identified by high throughput screening. The molecules of the series have been optimized from a high quality starting point hit to afford excellent developability, tolerability, and efficacy profiles, leading to identification of a clinical candidate. Unusually for an ion channel target, this optimization was integrated with regular generation of ligand-bound crystal structures and uncovered a novel chemotype with a unique and highly conserved mode of interaction via a trifluoromethyl group.
Asunto(s)
Indazoles/síntesis química , Receptores AMPA/fisiología , Regulación Alostérica , Animales , Calcio/metabolismo , Cristalografía por Rayos X , Perros , Ensayos Analíticos de Alto Rendimiento , Humanos , Técnicas In Vitro , Indazoles/farmacocinética , Indazoles/farmacología , Ligandos , Macaca fascicularis , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Técnicas de Placa-Clamp , Multimerización de Proteína , Ratas , Ratas Sprague-Dawley , Receptores AMPA/química , Proteínas Recombinantes/química , Solubilidad , Relación Estructura-Actividad , Porcinos , Porcinos EnanosRESUMEN
A series of AMPA receptor positive allosteric modulators has been optimized from poorly penetrant leads to identify molecules with excellent preclinical pharmacokinetics and CNS penetration. These discoveries led to 17i, a potent, efficacious CNS penetrant molecule with an excellent pharmacokinetic profile across preclinical species, which is well tolerated and is also orally bioavailable in humans.
Asunto(s)
Indenos/síntesis química , Piridinas/síntesis química , Receptores AMPA/fisiología , Sulfonamidas/síntesis química , Administración Oral , Regulación Alostérica , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Barrera Hematoencefálica/metabolismo , Callithrix , Línea Celular , Cristalografía por Rayos X , Perros , Humanos , Indenos/farmacocinética , Indenos/farmacología , Macaca fascicularis , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Unión Proteica , Estructura Terciaria de Proteína , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
A series of 5-(piperidinylethyloxy)quinoline 5-HT(1) receptor ligands have been studied by elaboration of the series of dual 5-HT(1)-SSRIs reported previously. These new compounds display a different pharmacological profile with potent affinity across the 5-HT(1A), 5-HT(1B) and 5-HT(1D) receptors and selectivity against the serotonin transporter. Furthermore, they have improved pharmacokinetic profiles and CNS penetration.
Asunto(s)
Receptores de Serotonina/metabolismo , Serotoninérgicos/metabolismo , Administración Oral , Disponibilidad Biológica , Ligandos , Serotoninérgicos/farmacocinéticaRESUMEN
Investigation of halogen substitution in lead compound 1 has led to the identification of analogues which combine high affinity for 5-HT(1A) receptors and potent serotonin reuptake inhibitory activity. Several compounds show an improved selectivity over 5-HT(1B) and 5-HT(1D) receptors and a superior pharmacokinetic profile in the rat.
Asunto(s)
Benzoxazinas/síntesis química , Benzoxazinas/farmacología , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Callithrix , Línea Celular , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Cobayas , Humanos , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Piperazinas/farmacología , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Receptor de Serotonina 5-HT1D/efectos de los fármacos , Sinaptosomas/efectos de los fármacosRESUMEN
We report here the discovery of a class of MCH R1 ligands based on a biphenyl carboxamide template. A docked-in model is presented indicating key interactions in the putative binding site of the receptor. Parallel high throughput synthetic techniques were utilised to allow rapid exploration of the structure-activity relationship around this template, leading to compound SB-568849 which possessed good receptor affinity and selectivity. This compound proved to be an antagonist with stability in vivo, an acceptable brain-blood ratio and oral bioavailability.
Asunto(s)
Amidas/química , Amidas/farmacología , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacocinética , Animales , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Bovinos , Biología Computacional , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Receptores de Somatostatina/química , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Azufre/químicaRESUMEN
Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.