Design, synthesis and evaluation of novel 2-amino-3-(naphth-2-yl)propanoic acid derivatives as potent inhibitors of platelet aggregation

Zhouling Xie; Benimana Oscar; Lulu Zhao; Xue Ding; Chen Cao; Sen Feng; Han Li; Chen Pan; Ziyi Bian; Yang Li; Weijun Wang; Yi Kong; Zhiyu Li

doi:10.1016/j.ejmech.2016.09.032

Design, synthesis and evaluation of novel 2-amino-3-(naphth-2-yl)propanoic acid derivatives as potent inhibitors of platelet aggregation

Eur J Med Chem. 2017 Jan 5:125:197-209. doi: 10.1016/j.ejmech.2016.09.032. Epub 2016 Sep 10.

Authors

Zhouling Xie¹, Benimana Oscar¹, Lulu Zhao¹, Xue Ding², Chen Cao¹, Sen Feng¹, Han Li¹, Chen Pan¹, Ziyi Bian¹, Yang Li¹, Weijun Wang¹, Yi Kong³, Zhiyu Li⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
² School of Life Science & Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
³ School of Life Science & Technology, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: yikong668@163.com.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhiyuli@cpu.edu.cn.

PMID: 27662032
DOI: 10.1016/j.ejmech.2016.09.032

Abstract

Based upon LX2421, a previously identified antiplatelet aggregation agent, a series of novel 2-amino-3-(naphth-2-yl)propanoic acid derivatives were designed, synthesized and evaluated. Among them, compounds LX14 and LX25 were identified as promising antiplatelet aggregation agents. The in vitro biologic study demonstrated that LX14 can block platelet aggregation induced by four different inducers and displays comparable potency in inhibiting GPIIb/IIIa receptor in comparison with Tirofiban. In addition, LX14 has much lower risk of bleeding than Tirofiban and shows significant antithrombotic activity in vivo. Taking together, the results indicated that LX14 is a promising GPIIb/IIIa receptor antagonist against platelet aggregation worthy of further evaluation.

Keywords: Antiplatelet aggregation; Antithrombotic activity; Bleeding risk; GPIIb/IIIa receptor; Inhibitor; Naphthalene derivatives.

MeSH terms

Drug Design
Hemorrhage / chemically induced
Hemorrhage / drug therapy
Humans
Platelet Aggregation / drug effects*
Platelet Aggregation Inhibitors / chemistry
Platelet Aggregation Inhibitors / pharmacology
Platelet Glycoprotein GPIIb-IIIa Complex / antagonists & inhibitors
Propionates / chemical synthesis
Propionates / pharmacology*
Thrombosis / drug therapy
Thrombosis / prevention & control

Substances

Platelet Aggregation Inhibitors
Platelet Glycoprotein GPIIb-IIIa Complex
Propionates