RESUMO
From an azaindole lead, identified in high throughput screen, a series of potent bis-azaindole inhibitors of IGF1-R have been synthesized using rational drug design and SAR based on a in silico binding mode hypothesis. Although the resulting compounds produced the expected improved potency, the model was not validated by the co-crystallization experiments with IGF1-R.
Assuntos
Indóis/química , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/síntese química , Indóis/farmacocinética , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Relação Estrutura-AtividadeRESUMO
(E)-3-(2-Carboxy-2-phenylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acid, 1, is a potent and selective antagonist of the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Using 3D comparative molecular field analysis (CoMFA) to guide the synthetic effort, a series of aryl diacid analogues of 1 were synthesized to optimize in vivo potency, duration of action, and binding activity. It was found that the incorporation of a substituted aromatic with an electron withdrawing group or a heterocyclic group at the 2-position of the 3-propenyl moiety of 1 gave compounds with better affinity and potency in the murine stroke model. Ultimately this led to the discovery of 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, 19, as a new potent selective glycine-site NMDA receptor antagonist.
Assuntos
Ácidos Carboxílicos/síntese química , Glicina/metabolismo , Indóis/química , Fenilacetatos/química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/química , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Sítios de Ligação , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , GMP Cíclico/biossíntese , Técnicas In Vitro , Indóis/síntese química , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Modelos Moleculares , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fenilacetatos/síntese química , Fenilacetatos/farmacologia , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Convulsões/etiologia , Convulsões/prevenção & controle , Estereoisomerismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/patologiaRESUMO
Continuing studies into the utility of poly(ethylene glycol) (PEG)-supported triarylphosphines as functional polymer reagents in liquid-phase organic synthesis (LPOS) are being pursued. This report describes the synthesis and NMR characterization of an aryl-alkyl ether-linked PEG-triarylphosphine derivative (2) and its subsequent application in LPOS. The utility of 2 as a mild stoichiometric reagent for ozonide reduction has been demonstrated, and a direct comparison between 2, a Merrifield resin-bound triarylphosphine derivative, and a solution-phase triphenylphosphine reagent revealed that the highest observed yields occur under liquid-phase conditions. Transformation of phosphine 2 into a phosphonium salt (3) then allowed the inherent aqueous solubility of PEG-functionalized moieties to be exploited by enabling a Wittig reaction, between a range of aldehydes and 3, to occur under mildly basic aqueous conditions. This led to the generation of substituted stilbenes in good to excellent yields. Finally, regeneration of 2 was achieved by reduction of the PEG-supported triphenylphosphine oxide byproduct 4 with alane (100% conversion, 75% yield). This combination of reaction, recovery, and regeneration expands the utility of PEG-supported triarylphosphine reagents across the spectra of both organic chemistry and solution-phase combinatorial strategies.
