Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors.
5-(1,3,4-Oxadiazol-2-yl)pyrimidine derivative 1 was identified as a new class of FLT3 inhibitor from our compound library. With the aim of enhancement of antitumor activity of 2 prepared by minor modification of 1, structure optimization of side chains at the 2-, 4-, and 5-positions of the pyrimidine ring of 2 was performed to improve the metabolic stability. Introduction of polar substituents on the 1,3,4-oxadiazolyl group contributed to a significant increase in the metabolic stability. As a result, a series of compounds showed increased efficacy against MOLM-13 xenograft model in mice by oral administration.
Ishida
Hiroshi
H
Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd, 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan. hiroshi.ishida@kyowa.co.jp
Isami
Shoichi
S
Matsumura
Tsutomu
T
Umehara
Hiroshi
H
Yamashita
Yoshinori
Y
Kajita
Jiro
J
Fuse
Eiichi
E
Kiyoi
Hitoshi
H
Naoe
Tomoki
T
Akinaga
Shiro
S
Shiotsu
Yukimasa
Y
Arai
Hitoshi
H
D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D016513:Mice, SCID; D008956:Models, Chemical; D009368:Neoplasm Transplantation; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D010069:Oxadiazoles; D011743:Pyrimidines; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3