RESUMO
A series of 2-(thioalkyl)pentanedioic acids were synthesized and evaluated as inhibitors of glutamate carboxypeptidase II (GCP II, EC 3.4.17.21). The inhibitory potency of these thiol-based compounds against GCP II was found to be dependent on the number of methylene units between the thiol group and pentanedioic acid. A comparison of the SAR of the thiol-based inhibitors to that of the phosphonate-based inhibitors provides insight into the role of each of the two zinc-binding groups in GCP II inhibition. The most potent thiol-based inhibitor, 2-(3-mercaptopropyl)pentanedioic acid (IC(50) = 90 nM), was found to be orally bioavailable in rats and exhibited efficacy in an animal model of neuropathic pain following oral administration.
Assuntos
Analgésicos/síntese química , Carboxipeptidases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Glutaratos/síntese química , Compostos de Sulfidrila/síntese química , Administração Oral , Analgésicos/química , Analgésicos/farmacologia , Animais , Disponibilidade Biológica , Carboxipeptidases/química , Constrição Patológica/complicações , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glutamato Carboxipeptidase II , Glutaratos/química , Glutaratos/farmacologia , Temperatura Alta , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Masculino , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/complicações , Ratos , Ratos Sprague-Dawley , Nervo Isquiático , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologiaRESUMO
Relative rates of reactions of MeLi with benzophenones in diethyl ether at 0 degrees C that furnish methyldiarylmethanols were determined using slow addition of a MeLi solution to solutions containing an excess of two benzophenones. The additions exhibit a Hammett rho of 0.94.
RESUMO
An organozincate of composition Et3ZnLi and di-tert-butyl ketone react in toluene to form (after hydrolysis) ethyl-di-tert-butylmethanol. The rate is proportional to approximately [Et3ZnLi](-0.5)[ketone](1) when the initial concentration of Et3ZnLi is greater than that of the ketone but proportional to [Et3ZnLi](1)[ketone](-1) when the initial concentration of ketone is greater than that of Et3ZnLi. The rate of addition of Et3ZnK to di-tert-butyl ketone is <10(-4) that of Et3ZnLi.