RESUMO
A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Fenilalanina/análogos & derivados , Piridazinas/síntese química , Animais , Disponibilidade Biológica , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Sulfato de Dextrana , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Granulócitos/efeitos dos fármacos , Granulócitos/fisiologia , Humanos , Imunoglobulinas/metabolismo , Técnicas In Vitro , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Células K562 , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Mucoproteínas/metabolismo , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Ratos , Relação Estrutura-Atividade , Veias Umbilicais/citologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.
Assuntos
Aminoácidos Cíclicos/química , Compostos Aza/síntese química , Compostos Aza/farmacologia , Integrina alfa4beta1/antagonistas & inibidores , Integrinas/antagonistas & inibidores , Animais , Compostos Aza/química , Feminino , Integrina alfa4beta1/metabolismo , Integrinas/metabolismo , Leucocitose , Linfócitos/efeitos dos fármacos , Masculino , Camundongos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.