期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 17, 页码 10045-10060出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01161
关键词
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资金
- National Natural Science Foundation of China [81973173]
- Jiangsu Province Funds for Excellent Young Scientists [BK20170088]
- Open Project of State Key Laboratory of Natural Medicines [SKLNMZZCX201803]
- National Major Science and Technology Project of China [2017ZX09302003]
- Six Talent Peaks Project [YY-023]
- 333 Project of Jiangsu Province
The design and discovery of a new series of (5-alkynyl-3-hydroxypicolinoyl)glycine inhibitors of prolyl hydroxylase (PHD) are described. These compounds showed potent in vitro inhibitory activity toward PHD2 in a fluorescence polarization-based assay. Remarkably, oral administration of 17, with an IC50 of 64.2 nM toward PHD2, was found to stabilize HIF-alpha, elevate erythropoietin (EPO), and alleviate anemia in a cisplatin-induced anemia mouse model with an oral dose of 25 mg/kg. Rat and dog studies showed that 17 has good pharmacokinetic properties, with oral bioavailabilities of 55.7 and 54.0%, respectively, and shows excellent safety profiles even at a high dose of 200 mg/kg in these animals. Based on these results, 17 is currently being evaluated in a phase I clinical trial for anemia.
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