(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling

doi:10.1016/j.bmc.2014.09.051

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	(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling
	Wang, Sinan; Su, Mingbo; Wang, Jiang; Li, Zeng; Zhang, Lei; Ji, Xun; Li, Jingya; Li, Jia; Liu, Hong
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2014-12-01
卷号	22 期号:23 页码:6684-6693
关键词	DPP-4 Type 2 diabetes Inhibitor Binding mode Oral bioavailability
ISSN号	0968-0896
DOI	10.1016/j.bmc.2014.09.051
文献子类	Article
英文摘要	A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC(50)s of 0.07, 0.07, 0.14, and 0.17 mu M, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F = 96.3%, t(1/2) = 10.5 h). (C) 2014 Elsevier Ltd. All rights reserved.
资助项目	National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[81302633] ; National Natural Science Foundation of China[81025017] ; National S&T Major Projects[2012ZX09103101-072] ; National S&T Major Projects[2012ZX09301001-005] ; National S&T Major Projects[2013ZX09507-001] ; National S&T Major Projects[2014ZX09507002-001]
WOS关键词	TYPE-2 DIABETES-MELLITUS ; GLUCAGON-LIKE PEPTIDE-1 ; DPP-4 INHIBITOR ; IV INHIBITOR ; HIGHLY POTENT ; SITAGLIPTIN ; VILDAGLIPTIN ; POLYPEPTIDE ; DEGRADATION ; SAXAGLIPTIN
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
出版者	PERGAMON-ELSEVIER SCIENCE LTD
WOS记录号	WOS:000345287300015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276819]
专题	国家新药筛选中心药物化学研究室药物安全性评价中心
通讯作者	Li, Jia
作者单位	Chinese Acad Sci, CAS Key Lab Receptor Res, Shanghai Inst Mat Med, Shanghai Inst Biol Sci, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wang, Sinan,Su, Mingbo,Wang, Jiang,et al. (R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2014,22(23):6684-6693.
APA	Wang, Sinan.,Su, Mingbo.,Wang, Jiang.,Li, Zeng.,Zhang, Lei.,...&Liu, Hong.(2014).(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling.BIOORGANIC & MEDICINAL CHEMISTRY,22(23),6684-6693.
MLA	Wang, Sinan,et al."(R)-3-Amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: Design, synthesis, biological evaluation, and molecular modeling".BIOORGANIC & MEDICINAL CHEMISTRY 22.23(2014):6684-6693.