Studies on cerebral protective agents. III. Novel 4-arylpyrimidine derivatives with anti-anoxic and anti-lipid peroxidation activities. (3).
Novel 4-arylpyrimidine derivatives, bearing an amino moiety in the C-5 or C-6 position of the pyrimidine ring, were synthesized and tested for anti-anoxic (AA) activity in mice. Among them, 6,7-dihydro-6-[2-(dimethylamino)-ethyl]-4-(3-nitrophenyl)-2-phenyl-5H- pyrrolo[3,4-d]pyrimidine-5-one (2a, FR 75469) and 6-methyl-5-(4-methyl-piperazin-1-ylmethyl)-4-(3-nitrophenyl) - 2-phenylpyrimidine (4c, FR 72707) had comparable potency 10-100 mg/kg, i.p. and p.o.) to that of 6-methyl-5-(4-methylpiperazin-1-ylcarbonyl)-4-(3-nitrophenyl )-2-phenylpyrimidine (FK 360). These were also effective on anti-lipid peroxidation (ALP) assay and arachidonate-induced cerebral edema in rats. Structure-activity relationship in regard to AA activity of this series of compounds are discussed. Three-dimensional molecular electrostatic potentials (3D-MEP) around the nitrogenous basic moiety of FK 360 and 5-acetyl-6-(2-dimethylaminoethyl)-4-(3-nitrophenyl)-2- phenylpyrimidine (5f) were compared, and both electrostatic potential maps were similar.
Kuno
A
A
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Katsuta
K
K
Sakai
H
H
Ohkubo
M
M
Sugiyama
Y
Y
Takasugi
H
H
D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002534:Hypoxia, Brain / Q000517:prevention & control*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D011743:Pyrimidines