RESUMO
Peptidomimetic compounds possessing a caprolactam ring constraint were prepared and evaluated as interleukin-1beta converting enzyme (ICE) inhibitors. The caprolactam ring was used to constrain the P3 region of our inhibitors. This strategy proved to be effective for the synthesis of ICE inhibitors, maintaining key hydrogen bond interactions with the enzyme and invoking a preferred conformation for binding. Several compounds exhibited IC(50) values less than 10nM in a caspase-1 enzyme assay and less than 100nM in a THP-1 whole cell assay measuring IL-1beta production. Two compounds, 13c and 13j, were found to have good oral bioavailability (>50%) in rats when administered as prodrugs.
Assuntos
Caprolactama/síntese química , Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Serpinas/síntese química , Proteínas Virais/síntese química , Animais , Disponibilidade Biológica , Caprolactama/química , Caprolactama/farmacologia , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligação de Hidrogênio , Interleucina-1beta/metabolismo , Masculino , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Serpinas/farmacologia , Relação Estrutura-Atividade , Proteínas Virais/farmacologiaRESUMO
An 8,5-fused bicyclic peptidomimetic ring system generated by a stereoselective ring metathesis reaction was elaborated into potent inhibitors of interleukin-1beta converting enzyme (ICE, caspase-1). Multiple compounds were found that exhibited ICE IC50 values < 10 nM and were selective over caspase-3 and caspase-8. These active analogs generally possessed good activity (IC50 values < 100 nM) in a whole cell assay measuring IL-1beta production. Pharmacokinetic analysis of the ethyl acetal prodrug form of a selected active lead revealed a compound with a reasonable plasma half-life (1.1 h) and good oral bioavailability (30%).
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Caspase , Peptídeos Cíclicos/farmacologia , Animais , Disponibilidade Biológica , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Concentração Inibidora 50 , Mimetismo Molecular , Peptídeos Cíclicos/síntese química , Pró-Fármacos/farmacocinética , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of monocyclic thiazepine inhibitors of interleukin-1beta converting enzyme (ICE) were synthesized in eight steps from commercially available intermediates. In vitro biological evaluation showed the thiazepines to be moderately potent ICE inhibitors, with the most active compound exhibiting an IC50 value of 30 nM in an enzyme inhibition assay. Compounds of this class possessed good selectivity against the related enzymes caspase-3 and caspase-8.
Assuntos
Inibidores de Caspase , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Tiazepinas/síntese química , Tiazepinas/farmacologia , Caspase 1/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/química , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Tiazepinas/químicaRESUMO
Novel 1-(2-acylhydrazinocarbonyl)cycloalkyl carboxamides were designed as peptidomimetic inhibitors of interleukin-1beta converting enzyme (ICE). A short synthesis was developed and moderately potent ICE inhibitors were identified (IC(50) values <100 nM). Most of the synthesized examples were selective for ICE versus the related cysteine proteases caspase-3 and caspase-8, although several dual-acting inhibitors of ICE and caspase-8 were identified. Several of the more potent ICE inhibitors were also shown to inhibit IL-1beta production in a whole cell assay (IC(50) < 500 nM).
Assuntos
Amidas/síntese química , Amidas/farmacologia , Aminoimidazol Carboxamida/síntese química , Inibidores de Caspase , Hidrazinas/síntese química , Hidrazinas/farmacologia , Aminoimidazol Carboxamida/análogos & derivados , Caspase 8 , Química Farmacêutica/métodos , Cisteína Endopeptidases/metabolismo , Indústria Farmacêutica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Humanos , Concentração Inibidora 50 , Modelos QuímicosRESUMO
Two novel 8,6-fused bicyclic peptidomimetic ring systems were synthesized utilizing olefin metathesis as the key reaction for the formation of the eight-membered ring. Both peptidomimetic scaffolds were further elaborated into potent ICE inhibitors, with numerous compounds exhibiting caspase-1 IC(50)s less than 10nM.
Assuntos
Biomimética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Inibidores de Caspase , Inibidores Enzimáticos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Inibidores Enzimáticos/síntese química , Humanos , Indicadores e Reagentes , Modelos Moleculares , Conformação MolecularRESUMO
A novel diazocan containing dipeptide mimetic was synthesized via reductive N-N bond cleavage of a pyrazolidino-pyrazolidine using Raney-Ni and evaluated as an ICE inhibitor. This versatile 8-membered ring containing scaffold possesses an N-5 ring nitrogen that was used to explore structure-activity relationships in a cell-based assay measuring inhibition of interleukin-1beta.
Assuntos
Dipeptídeos/síntese química , Interleucina-1/antagonistas & inibidores , Peptídeos Cíclicos/síntese química , Inibidores de Caspase , Dipeptídeos/química , Dipeptídeos/farmacologia , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Interleucina-1/biossíntese , Conformação Molecular , Mimetismo Molecular , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Pirazóis/química , Relação Estrutura-AtividadeRESUMO
The application of a tricyclic pyrrolopyrimidinone scaffold for the synthesis of peptidomimetic inhibitors of interleukin-1beta-converting enzyme (ICE) is reported. The synthesis of the tricyclic scaffold and conversion of it to a variety of target ICE inhibitors were accomplished in 4-5 steps. In vitro biological evaluation of the tricyclic pyrrolopyrimidinones revealed fair to good ICE inhibitors, with the most active compound exhibiting an IC50 of 14 nM in a caspase-1 enzyme binding assay.