New gamma-fluoromethotrexates modified in the pteridine ring: synthesis and in vitro immunosuppressive activity.
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.
Kokuryo
Y
Y
Shionogi Research Laboratories, Shionogi & Co. Ltd., Fukushima-ku, 553-0002, Osaka, Japan.
Nakatani
T
T
Kakinuma
M
M
Kabaki
M
M
Kawata
K
K
Kugimiya
A
A
Kawada
K
K
Matsumoto
M
M
Suzuki
R
R
Ohtani
M
M
D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D015394:Molecular Structure; D011621:Pteridines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects
D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; D007166:Immunosuppressive Agents; D008934:Mitogens; C412313:N-(4-(3-(2,4-diamino-7H-pyrrolo(2,3-d)-pyrimidin-5-yl)-1-methylpropyl)benzoyl)-gamma-fluoroglutamic acid; D011621:Pteridines; D011743:Pyrimidines; C036539:fluoresceinated methotrexate; D018698:Glutamic Acid; D008727:Methotrexate