RESUMEN
The highly specific S1 serine protease factor D (FD) plays a central role in the amplification of the complement alternative pathway (AP) of the innate immune system. Genetic associations in humans have implicated AP activation in age-related macular degeneration (AMD), and AP dysfunction predisposes individuals to disorders such as paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). The combination of structure-based hit identification and subsequent optimization of the center (S)-proline-based lead 7 has led to the discovery of noncovalent reversible and selective human factor D (FD) inhibitors with drug-like properties. The orally bioavailable compound 2 exerted excellent potency in 50% human whole blood in vitro and blocked AP activity ex vivo after oral administration to monkeys as demonstrated by inhibition of membrane attack complex (MAC) formation. Inhibitor 2 demonstrated sustained oral and ocular efficacy in a model of lipopolysaccharide (LPS)-induced systemic AP activation in mice expressing human FD.
Asunto(s)
Factor D del Complemento/antagonistas & inhibidores , Vía Alternativa del Complemento/efectos de los fármacos , Prolina/análogos & derivados , Prolina/farmacología , Administración Oral , Animales , Síndrome Hemolítico Urémico Atípico/tratamiento farmacológico , Síndrome Hemolítico Urémico Atípico/inmunología , Factor D del Complemento/inmunología , Complejo de Ataque a Membrana del Sistema Complemento/antagonistas & inhibidores , Complejo de Ataque a Membrana del Sistema Complemento/inmunología , Femenino , Haplorrinos , Humanos , Macaca fascicularis , Degeneración Macular/tratamiento farmacológico , Degeneración Macular/inmunología , Masculino , Ratones , Prolina/administración & dosificación , Prolina/farmacocinéticaRESUMEN
In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.