hDHFR-NADPH-dhf249(hDHFR-NADPH-dhf249) - 药物靶点：DHFR x Folate x TYMS_专利_临床

概要

基本信息

药物类型

小分子化药

别名

N-{4-[2-amino-6-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidin-5-yl)sulfanyl]benzoyl}-L-glutamic acid

靶点

DHFR x Folate x TYMS

作用机制

DHFR抑制剂(二氢叶酸还原酶抑制剂)、叶酸抑制剂、TYMS抑制剂(胸苷酸合成酶抑制剂)

治疗领域-

在研适应症-

非在研适应症-

原研机构

Hauptman Woodward Medical Research Institute, Inc.

在研机构

Hauptman Woodward Medical Research Institute, Inc.

非在研机构-

最高研发阶段药物发现

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 hDHFR-NADPH-dhf249 相关的临床结果

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100 项与 hDHFR-NADPH-dhf249 相关的转化医学

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100 项与 hDHFR-NADPH-dhf249 相关的专利（医药）

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1

项与 hDHFR-NADPH-dhf249 相关的文献（医药）

2005-11-01·Journal of Medicinal Chemistry1区 · 医学

Synthesis of N-{4-[(2,4-Diamino-5-methyl-4,7-dihydro-3H- pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-l-glutamic Acid and N-{4-[(2-Amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin- 6-yl)thio]benzoyl}-l-glutamic Acid as Dual Inhibitors of Dihydrofolate Reductase and Thymidylate Synthase and as Potential Antitumor Agents

1区 · 医学

Article

作者: McGuire, John J. ; Gangjee, Aleem ; Kisliuk, Roy L. ; Lin, Xin

Two novel classical antifolates N-{4-[(2,4-diamino-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 3 and N-{4-[(2-amino-4-oxo-5-methyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-6-yl)thio]benzoyl}-L-glutamic acid 4 were designed, synthesized, and evaluated as antitumor agents. Compounds 3 and 4 were obtained from 2,4-diamino-5-methylpyrrolo[2,3-d]pyrimidine 7 and 2-amino-4-oxo-5-methylpyrrolo[2,3-d]pyrimidine 12, respectively, in a concise three-step sequence. Compound 3 is the first example, to our knowledge, of a 2,4-diamino classical antifolate that has potent inhibitory activity against both human dihydrofolate reductase (DHFR) and human thymidylate synthase (TS). Compound 4 was a dual DHFR-TS inhibitor against the bifunctional enzyme derived from Toxoplasma gondii (tg). Further evaluation of the mechanism of action of 3 implicated DHFR as its primary intracellular target. Both 3 and 4 were folylpolyglutamate synthetase (FPGS) substrates. Compound 3 also inhibited the growth of several human tumor cell lines in culture with GI50 < 10(-8) M. This study shows that the pyrrolo[2,3-d]pyrimidine scaffold is conducive to dual DHFR-TS and tumor inhibitory activity, and the potency is determined by the 4-position substituent.

100 项与 hDHFR-NADPH-dhf249 相关的药物交易

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