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发现4-芳基酰胺基-3-甲基异恶唑衍生物作为新型FMS激酶抑制剂

Discovery of 4-arylamido 3-methyl isoxazole derivatives as novel FMS kinase inhibitors.

作者信息

Im Daseul, Jung Kyungjin, Yang Songyi, Aman Waqar, Hah Jung-Mi

机构信息

Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 426-791, Republic of Korea.

Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University 55 Hanyangdaehak-ro, Sangnok-gu, Ansan, Kyeonggi-do, 426-791, Republic of Korea.

出版信息

Eur J Med Chem. 2015 Sep 18;102:600-10. doi: 10.1016/j.ejmech.2015.08.031. Epub 2015 Aug 18.

DOI:10.1016/j.ejmech.2015.08.031
PMID:26318067
Abstract

A series of 4-arylamido 3-methyl isoxazoles were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Most compounds showed selective antiproliferative activity toward the U937 cell line and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide 5a-b, 6a-o and urea 7a-n, 8a-g with hydrophobic moieties, and one of the most potent inhibitor 6a, 5-methyl-N-(2-methyl-5-(3-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzamido)phenyl)isoxazole-4-carboxamide was found to be very potent inhibitor of FMS kinase (GI50 = 0.016 μM, IC50 = 9.95 nM) with excellent selectivity profiles and is a promising candidate for further development in therapeutics for cancer.

摘要

合成了一系列4-芳基酰胺基3-甲基异恶唑，并评估了它们对A375P黑色素瘤细胞系和U937造血细胞系的抗增殖活性。大多数化合物对U937细胞系表现出选择性抗增殖活性，且活性优于参考标准药物索拉非尼。制备了带有疏水基团的酰胺5a-b、6a-o和脲7a-n、8a-g衍生物，其中最有效的抑制剂之一6a，即5-甲基-N-(2-甲基-5-(3-(4-甲基哌嗪-1-基)-5-(三氟甲基)苯甲酰胺基)phenyl)异恶唑-4-甲酰胺，被发现是FMS激酶的强效抑制剂（GI50 = 0.016 μM，IC50 = 9.95 nM），具有优异的选择性，是癌症治疗进一步开发的有前景的候选药物。

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