RESUMO
Antagonism of the mGluR2 receptor has the potential to provide therapeutic benefit to cognitive disorders by elevating synaptic glutamate, the primary excitatory neurotransmitter in the brain. Selective antagonism of the mGluR2 receptor, however, has so far been elusive, given the very high homology of this receptor with mGluR3, particularly at the orthosteric binding site. Given that inhibition of mGluR3 has been implicated in undesired effects, we sought to identify selective mGluR2 negative allosteric modulators. Herein we describe the discovery of the highly potent and selective class of mGluR2 negative allosteric modulators, 4-arylquinoline-2-carboxamides, following a successful HTS campaign and medicinal chemistry optimization, showing potent in vivo efficacy in rodent.
Assuntos
Descoberta de Drogas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Adjuvantes Anestésicos/toxicidade , Aminoácidos/farmacologia , Anfetaminas/farmacologia , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Ácido Glutâmico/metabolismo , Ensaios de Triagem em Larga Escala , Camundongos , Estrutura Molecular , Escopolamina/toxicidade , Relação Estrutura-AtividadeRESUMO
Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.
Assuntos
Adenosina/análogos & derivados , Desenho de Fármacos , Hidrolases/antagonistas & inibidores , S-Adenosil-Homocisteína , Adenosina/química , Adenosina/farmacologia , Animais , Química Encefálica , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Homocisteína/sangue , Ligação de Hidrogênio , Concentração Inibidora 50 , Modelos Moleculares , Ratos , S-Adenosil-Homocisteína/química , Especificidade por SubstratoRESUMO
From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Quinases/efeitos dos fármacos , Quinolonas/síntese química , Quinolonas/farmacologia , Apoptose/efeitos dos fármacos , Sítios de Ligação , Linhagem Celular Tumoral , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Fotoquímica , Proteínas Quinases/química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
Through a comparison of X-ray co-crystallographic data for 1 and 2 in the Chek1 active site, it was hypothesized that the affinity of the indolylquinolinone series (2) for Chek1 kinase would be improved via C6 substitution into the hydrophobic region I (HI) pocket. An efficient route to 6-bromo-3-indolyl-quinolinone (9) was developed, and this series was rapidly optimized for potency by modification at C6. A general trend was observed among these low nanomolar Chek1 inhibitors that compounds with multiple basic amines, or elevated polar surface area (PSA) exhibited poor cell potency. Minimization of these parameters (basic amines, PSA) resulted in Chek1 inhibitors with improved cell potency, and preliminary pharmacokinetic data are presented for several of these compounds.
Assuntos
Inibidores Enzimáticos/farmacologia , Indóis/química , Proteínas Quinases/efeitos dos fármacos , Quinolonas/química , Animais , Sítios de Ligação , Quinase 1 do Ponto de Checagem , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
Counterscreening compounds from a Merck PPAR program discovered lead 1, as a nanomolar LXR/PPAR dual agonist. SAR optimization developed a series of heterocyclic LXR agonists having excellent selectivity over all PPAR isoforms and possessing high LXR affinity and strong in vivo potency.
Assuntos
Proteínas de Ligação a DNA/agonistas , Desenho de Fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Ácidos/química , Aminação , Compostos de Anilina/química , Animais , HDL-Colesterol/sangue , Ciclização , Indóis/química , Receptores X do Fígado , Camundongos , Estrutura Molecular , Receptores Nucleares Órfãos , Relação Estrutura-AtividadeRESUMO
Liver X receptor (LXR) alpha and LXRbeta are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRalpha and LXRbeta by synthetic compounds. We here describe the effects of selective activation of LXRalpha or LXRbeta on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRalpha or LXRbeta with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRalpha (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRalpha, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRalpha and LXRbeta-deficient mice. Our data lend further experimental support to the hypothesis that LXRbeta-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.