RESUMO
The identification of a new series of RORc inverse agonists is described. Comprehensive structure-activity relationship studies of this reversed sulfonamide series identified potent RORc inverse agonists in biochemical and cellular assays which were also selective against a panel of nuclear receptors. Our work has contributed a compound that may serve as a useful in vitro tool to delineate the complex biological pathways involved in signalling through RORc. An X-ray co-crystal structure of an analogue with RORc has also provided useful insights into the binding interactions of the new series.
Assuntos
Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/agonistas , Sulfonamidas/química , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Citocinas/biossíntese , Agonismo Inverso de Drogas , Células HEK293 , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/toxicidadeRESUMO
This report describes the effect of replacing the central basic amine present in many known 5-HT(2A) ligands with an aromatic residue. We targeted the isomeric phenethylpyridines 2 and 3 and these compounds proved to be excellent leads, possessing good 5-HT(2A) receptor binding affinity and selectivity over the 5-HT(2C) subtype. Optimization of one isomer led to the identification of 25, a compound with sub-nanomolar 5-HT(2A) affinity and selectivity over 5-HT(2C) of greater than 4600-fold.
Assuntos
Química Farmacêutica/métodos , Piridinas/química , Piridinas/síntese química , Receptor 5-HT2A de Serotonina/química , Antagonistas da Serotonina/química , Antagonistas da Serotonina/síntese química , Animais , Desenho de Fármacos , Humanos , Cinética , Ligantes , Modelos Químicos , Conformação Molecular , Piridinas/farmacologia , Ratos , Antagonistas da Serotonina/farmacologia , Sulfonas/químicaRESUMO
Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.
Assuntos
Piridazinas/síntese química , Receptores de GABA-A/efeitos dos fármacos , Animais , Linhagem Celular , Humanos , Técnicas In Vitro , Ligantes , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Técnicas de Patch-Clamp , Subunidades Proteicas/fisiologia , Piridazinas/farmacocinética , Piridazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/fisiologia , Proteínas Recombinantes/metabolismo , Relação Estrutura-AtividadeRESUMO
On the basis of a spirocyclic ether screening lead, a series of acyclic sulfones have been identified as high-affinity, selective 5-HT(2A) receptor antagonists. Bioavailability lacking in the parent, 1-(2-(2,4-difluorophenyl)ethyl)-4-(phenylsulfonyl)piperidine (12), was introduced by using stability toward rat liver microsomes as a predictor of bioavailability. By this means, the 4-cyano- and 4-carboxamidophenylsulfonyl derivatives 26 and 31 were identified as orally bioavailable, brain-penetrant analogues suitable for evaluation in animal models. Bioavailability was also attainable by N substitution leading to the N-phenacyl derivative 35. IKr activity detected through counterscreening was reduced to insignificant levels in vivo with the latter compound.