Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors

doi:10.1021/acs.jmedchem.8b00819

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 国家新药筛选中心

	Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors
	Li, Daqiang 3; Zhang, Xiaotuan 4,6; Ma, Xiaodong 1; Xu, Lei 5,6; Yu, Jianjun 3; Gao, Lixin 4; Hu, Xiaobei 4; Zhang, Jiankang 2; Dong, Xiaowu 3; Li, Jia4
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2018-10-25
卷号	61 期号:20 页码:9177-9204
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.8b00819
文献子类	Article
英文摘要	Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure- activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, beta 5) inhibitory potency (IC50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development.
资助项目	Zhejiang Provincial Natural Science Foundation of China[LZ15H300001] ; Science and Technology Commission of Shanghai Municipality[17431903000] ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020222]
WOS关键词	REFRACTORY MULTIPLE-MYELOMA ; SINGLE-AGENT CARFILZOMIB ; BIOLOGICAL EVALUATION ; 20S PROTEASOME ; PERIPHERAL NEUROPATHY ; STRUCTURAL CLASS ; DESIGN ; BORTEZOMIB ; IMMUNOPROTEASOMES ; BELACTOSIN
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000448754900013
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279528]
专题	国家新药筛选中心中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Liu, Tao; Zhou, Yubo; Hu, Yongzhou
作者单位	1.Anhui Univ Chinese Med, Sch Pharm, Dept Med Chem, Hefei 230031, Anhui, Peoples R China; 2.Zhejiang Univ, City Coll, Hangzhou 310015, Zhejiang, Peoples R China 3.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anti Canc Drug Res, Hangzhou 310058, Zhejiang, Peoples R China; 4.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201203, Peoples R China; 6.Univ Chinese Acad Sci, Grad Sch, 19A Yuquan Rd, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Li, Daqiang,Zhang, Xiaotuan,Ma, Xiaodong,et al. Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(20):9177-9204.
APA	Li, Daqiang.,Zhang, Xiaotuan.,Ma, Xiaodong.,Xu, Lei.,Yu, Jianjun.,...&Hu, Yongzhou.(2018).Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,61(20),9177-9204.
MLA	Li, Daqiang,et al."Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 61.20(2018):9177-9204.