RESUMO
A series of biaryl pyrazole and imidazole Liver X Receptor (LXR) partial agonists has been synthesized displaying LXRß selectivity. The LXRß selective partial agonist 18 was identified with potent induction of ATP binding transporters ABCA1 and ABCG1 in human whole blood (EC50=1.2µM, 55% efficacy). In mice 18 displayed peripheral induction of ABCA1 at 3 and 10mpk doses with no significant elevation of plasma or hepatic triglycerides at these doses, showing an improved profile compared to a full pan-agonist.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/sangue , Imidazóis/farmacologia , Fígado/efeitos dos fármacos , Receptores Nucleares Órfãos/agonistas , Pirazóis/farmacologia , Sulfonas/farmacologia , Animais , Agonismo Parcial de Drogas , Humanos , Imidazóis/química , Imidazóis/farmacocinética , Fígado/metabolismo , Receptores X do Fígado , Camundongos , Modelos Moleculares , Estrutura Molecular , Plasma/química , Pirazóis/química , Pirazóis/farmacocinética , Relação Estrutura-Atividade , Sulfonas/química , Sulfonas/farmacocinética , Distribuição Tecidual , Triglicerídeos/metabolismoRESUMO
Efforts to substitute the cyclopropane ring in a series of aryl cyclopropylnitriles led to the discovery of an operationally simple one-pot method for Knoevenagel condensation and subsequent Corey-Chaykovsky cyclopropanation giving diastereomerically pure products as a racemic mixture of enantiomers. Method development and results for variably substituted aryl acetonitriles and aldehydes in the reaction are reported. A concise synthesis of (±)-bicifadine in two steps is provided to demonstrate the utility of the method.
Assuntos
Aldeídos/química , Ciclopropanos/química , Nitrilas/química , Estrutura Molecular , EstereoisomerismoRESUMO
2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.
Assuntos
Ansiolíticos/síntese química , Antagonistas de Aminoácidos Excitatórios/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Ansiolíticos/química , Ansiolíticos/farmacologia , Ansiedade/psicologia , Encéfalo/metabolismo , Cálcio/metabolismo , Linhagem Celular , Antagonistas de Aminoácidos Excitatórios/química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Humanos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Structure-activity relationship studies leading to the discovery of novel mGlu5 receptor antagonists are described. These compounds show high in vitro potency, have good in vivo receptor occupancy, and a reasonable intravenous pharmacokinetic profile.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5RESUMO
The design, synthesis, and characterization of two potent, non-competitive radioligands, [3H]-methoxymethyl-MTEP and [3H]-methoxy-PEPy, that are selective for the mGlu5 receptor are described.
Assuntos
Piridinas/farmacologia , Compostos Radiofarmacêuticos/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Sítios de Ligação , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Físico-Química , Humanos , Técnicas In Vitro , Ligantes , Masculino , Piridinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Receptor de Glutamato Metabotrópico 5 , Tiazóis/farmacocinéticaRESUMO
Structure-activity relationship studies leading to the discovery of a new, orally active mGlu5 receptor antagonist are described. The title compound, 5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-2,3'-bipyridine, is highly potent in vitro, has good in vivo receptor occupancy, and is efficacious in the rat fear-potentiated startle model of anxiety following oral dosing.