RESUMO
The synthesis, SAR, and in vivo activity of inhibitors of delta-5 desaturase are described. Ring-constraint of the initial series provided access to a variety of in vitro active chemotypes, from which the indazole was selected. Examples from the indazole series displayed in vivo activity in reducing the enzymatic activity of liver delta-5 desaturase.
Assuntos
Amidas/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Ácidos Graxos Dessaturases/antagonistas & inibidores , Síndrome Metabólica/tratamento farmacológico , Amidas/síntese química , Amidas/química , Animais , Dessaturase de Ácido Graxo Delta-5 , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ácidos Graxos Dessaturases/metabolismo , Humanos , Fígado/enzimologia , Síndrome Metabólica/enzimologia , Síndrome Metabólica/metabolismo , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.
Assuntos
Glutamato Carboxipeptidase II/antagonistas & inibidores , Indóis/química , Inibidores de Proteases/química , Ácidos Carboxílicos , Avaliação Pré-Clínica de Medicamentos , Glutamato Carboxipeptidase II/metabolismo , Indóis/síntese química , Indóis/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Relação Estrutura-AtividadeRESUMO
Two representative glutamate carboxypeptidase II (GCP II) inhibitors, 2-(hydroxypentafluorophenylmethyl-phosphinoylmethyl)pentanedioic acid 2 and 2-(3-mercaptopropyl)pentanedioic acid 3, were synthesized in high optical purities (>97%ee). The two enantiomers of 2 were prepared from previously reported chiral intermediates, (R)- and (S)-2-(hydroxyphosphinoylmethyl)pentanedioic acid benzyl esters 8. The synthesis of (R)- and (S)-3 involves the hydrolysis of (R)- and (S)-3-(2-oxo-tetrahydro-thiopyran-3-yl)propionic acids, (R)- and (S)-11, the corresponding optically pure thiolactones delivered by chiral chromatographic separation of the racemic 11. GCP II inhibitory assay revealed that (S)-2 is 40-fold more potent than (R)-2. In contrast, both enantiomers of 3 inhibited GCP II with nearly equal potency. The efficacy observed in subsequent animal studies with these enantiomers correlated well with the inhibitory potency in a GCP II assay.
Assuntos
Glutamato Carboxipeptidase II/antagonistas & inibidores , Glutaratos/síntese química , Ácidos Fosfínicos/síntese química , Compostos de Sulfidrila/síntese química , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Isquemia Encefálica/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Constrição Patológica/complicações , Cristalografia por Raios X , Glutamato Carboxipeptidase II/química , Glutaratos/química , Glutaratos/farmacologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , L-Lactato Desidrogenase/metabolismo , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Dor/tratamento farmacológico , Dor/etiologia , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/etiologia , Ácidos Fosfínicos/química , Ácidos Fosfínicos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Compostos de Sulfidrila/química , Compostos de Sulfidrila/farmacologia , Técnicas de Cultura de TecidosRESUMO
δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydrothiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.
Assuntos
Inibidores Enzimáticos/síntese química , Glutamato Carboxipeptidase II/antagonistas & inibidores , Lactonas/síntese química , Pró-Fármacos/síntese química , Animais , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Lactonas/farmacologia , Lactonas/uso terapêutico , Microssomos Hepáticos/metabolismo , Neuralgia/tratamento farmacológico , RatosRESUMO
A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.