RESUMO
Reduction of the quinoline ring in an alpha(v)beta(3) antagonist yielded a 1,2,3,4-tetrahydro derivative as two diastereomers, the four isomers of which were separated by sequential chiral HPLC. Two isomers had significant alpha(V)beta(3) antagonist activity with improved oral bioavailability, relative to the corresponding quinoline derivative.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Integrina alfaVbeta3/metabolismo , Quinolinas/química , Quinolinas/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Quinolinas/administração & dosagem , RatosRESUMO
The synthesis and SAR of a new class of piperidine-based alphavbeta3/alphavbeta5 integrin antagonists is described. Replacement of an amide bond in a prototype isonipecotamide by a C-C isostere, and adjustment of the spacer length between the carboxylic acid and basic moieties, led to low nanomolar antagonists of alphavbeta3 and/or alphavbeta5 integrins with excellent selectivity versus alpha(IIb)beta3.