ANTIRHEUMATIC AGENTS .1. NOVEL METHOTREXATE DERIVATIVES BEARING AN INDOLINE MOIETY

Various novel methotrexate (MTX) derivatives bearing an indoline moiet y were synthesized and tested for biological activities using human pe ripheral blood mononuclear cell (hPBMC) and human synovial cells (hSC) derived from patients with rheumatoid arthritis (RA). Compounds havin g potent activity in vitro were further evaluated using an adjuvant ar thritis model in vivo. N-[1-(2,4-Diamino-6-pteridinylmethyl) indoline- 5-carbonyl]-L-glutamic acid 2f showed more potent activities than MTX in vitro and in vivo, and ridinylmethyl)indoline-5-carbonyl]-L-2-amino adipic acid 2d exhibited fairly good activities in vitro and considera ble activity in vivo. Compound 2d was, as expected, not sensitive to f olyl-polylglutamate synthetase (FPGS) and did not undergo polyglutamat ion, a process which may be responsible for a side-effect during MTX t herapy.