RESUMO
An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses to both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Flúor/metabolismo , Antagonistas do Ácido Fólico/síntese química , Metotrexato/análogos & derivados , Animais , Formação de Anticorpos/efeitos dos fármacos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/efeitos dos fármacos , Feminino , Metotrexato/uso terapêutico , Camundongos , Modelos Químicos , Ratos , Ratos Endogâmicos Lew , Estereoisomerismo , Linfócitos T/efeitos dos fármacosRESUMO
Our continuing program to develop new antifolate drugs useful against rheumatoid arthritis led us to modify the pteridine ring of gamma-fluoromethotrexate. Pyrrolopyrimidine derivatives 1e and 1t were found to exhibit potent suppressive effects on the responses of both T and B cells to mitogens, although tetrahydropyridopyrimidine derivatives 2e and 2t and quinazoline derivatives 3e, 3t and 4e showed very weak suppressive activities. Thus, conversion of the pteridine ring of gamma-fluoromethotrexate to a pyrrolopyrimidine ring led to a new potential antirheumatic compound.