Synthesis and biological activities of 2,4-diaminopteridine derivatives.
Substituted 2,4-diaminopteridine derivatives 10a-10l were prepared in moderate to good yield. Their structures were confirmed by 1H-NMR and MS spectroscopy, as well as by elemental analysis. Their inhibitory properties against inducible nitric oxide synthase (iNOS) were evaluated in vitro. Biological tests indicated that compound 10a, 10d, 10e, 10h, 10i, and 10l showed potent inhibitory activities similar to that of methotrexate (MTX), while the activities of compound 10b, 10c, 10f, 10g, 10j, and 10k are stronger than MTX. Two compounds, i. e., 10b (IC(50 )= 18.85 microM) and 10i (IC(50) = 24.08 microM) were further studied for their effect on septic shock in rats and immunologically liver injured mice (in vivo). The results demonstrated that 10b and 10i had the capacity to increase the blood pressure in septic shock and showed notable protective activities on immunological hepatic injury.
School of Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.
Fei
F
Ma
Gang
G
Lü
Wei-Fen
WF
Zhou
Qiu-Juan
QJ
Wang
Yi-Hua
YH
Zhang
Qi-Zheng
QZ
Yao
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D008107:Liver Diseases / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D011621:Pteridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology; D013329:Structure-Activity Relationship
C115021:2,4-diaminopteridine; D011621:Pteridines; D052247:Nitric Oxide Synthase Type II