RESUMO
A novel series of benzothiophene derivatives was discovered as phosphodiesterase 10A (PDE10A) inhibitors. Structure-activity relationship studies on high-throughput screening hit compound 1 led to the identification of 7-acetyl-3-methyl-N-(quinolin-2-yl)-1-benzothiophene-2-carboxamide (16), with potent inhibitory activity (PDE10A IC50â¯=â¯7.6â¯nM) and selectivity (>1300-fold selectivity over the other tested phosphodiesterases). In addition, a novel methyl-induced conformational alteration of the benzothiophene-2-carboxamide derivatives is reported.
Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Tiofenos/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
A series of compounds was discovered that induce the production of VGF mRNA in SH-SY5Y cells and exhibit cytoprotection under tunicamycin induced endoplasmic reticulum (ER) stress. The aminophenol ring and linker chain of the template SUN N8075 (1) was modified to yield compounds with higher efficacy and lower propensity for adverse effects.
Assuntos
Fatores de Crescimento Neural/biossíntese , Piperazinas/farmacologia , Linhagem Celular Tumoral , Citoproteção , Relação Dose-Resposta a Droga , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , RNA Mensageiro/biossíntese , Relação Estrutura-Atividade , Tunicamicina/farmacologiaRESUMO
Chiral diether ligand-controlled asymmetric conjugate addition of a lithium amide to cyclopentenecarboxylate and subsequent in situ alkylation gave a chiral cyclopentane derivative bearing a quaternary carbon with high enantio- and diastereoselectivity. The cyclopentane derivative was converted successfully to (-)-aspidospermidine.
Assuntos
Amidas/química , Alcaloides Indólicos/síntese química , Lítio/química , Quinolinas/síntese química , Alquilação , Aminação , Catálise , Ciclopentanos/síntese química , Ciclopentanos/química , Alcaloides Indólicos/química , Estrutura Molecular , Quinolinas/química , EstereoisomerismoRESUMO
A chiral ligand-controlled conjugate addition reaction of lithium benzyl(trimethylsilyl)amide with tert-butyl enoates gave the corresponding lithium enolates that were then treated with electrophiles, giving anti-alkylation products with high ee up to 98%. The benzyl group on the amino nitrogen was removed by the oxidation of secondary amines to imines and subsequent transoximation to give 3-aminoalkanoates in good yields. The products are the possible key intermediates of otamixaban and premafloxacin.
