Discovery of Potent Orally Active Protease-Activated Receptor 1 (PAR1) Antagonists Based on Andrographolide

Jun Liu; Bin Sun; Xiaoyu Zhao; Jie Xing; Yanhui Gao; Wenqiang Chang; Jianbo Ji; Hongbo Zheng; Changyi Cui; Aiguo Ji; Hongxiang Lou

doi:10.1021/acs.jmedchem.7b00951

Discovery of Potent Orally Active Protease-Activated Receptor 1 (PAR1) Antagonists Based on Andrographolide

J Med Chem. 2017 Aug 24;60(16):7166-7185. doi: 10.1021/acs.jmedchem.7b00951. Epub 2017 Aug 4.

Authors

Jun Liu¹, Bin Sun², Xiaoyu Zhao¹, Jie Xing¹, Yanhui Gao¹, Wenqiang Chang¹, Jianbo Ji¹, Hongbo Zheng¹, Changyi Cui¹, Aiguo Ji^{1

3}, Hongxiang Lou¹

Affiliations

¹ School of Pharmaceutical Sciences, Shandong University , Jinan 250012, China.
² National Glycoengineering Research Center, Shandong University , Jinan 250012, China.
³ Weihai International Biotechnology Research and Development Centre, Shandong University , Weihai 264209, China.

PMID: 28745507
DOI: 10.1021/acs.jmedchem.7b00951

Abstract

Protease-activated receptor-1 (PAR1), a G-protein-coupled receptor, plays a critical role in thrombin-mediated platelet aggregation. It is regarded as a promising antithrombosis target that is unlikely to result in bleeding. Here, we describe the synthesis of a series of novel PAR1 antagonists by borrowing the chiral fragment of andrographolide, an easily accessible natural molecule from Andrographis paniculata, to produce natural product/synthesis hybrids. An in vitro PAR1 inhibition assay and an in vivo pharmacokinetic profile led to the identification of compound 39 as the best PAR1 inhibitor. The further in vitro and ex vivo antiplatelet aggregation assays of compound 39 indicated that compound 39 was a potent antiplatelet agent. In addition, this compound is metabolically stable and displays a favorable pharmacokinetic profile with an elimination half-life of 3.1 h, which could be treated as a promising candidate for further clinical development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diterpenes / administration & dosage
Diterpenes / chemical synthesis
Diterpenes / pharmacokinetics
Diterpenes / pharmacology*
Guinea Pigs
HEK293 Cells
Humans
Male
Molecular Docking Simulation
Naphthalenes / administration & dosage
Naphthalenes / chemical synthesis
Naphthalenes / pharmacokinetics
Naphthalenes / pharmacology*
Platelet Aggregation Inhibitors / administration & dosage
Platelet Aggregation Inhibitors / chemical synthesis
Platelet Aggregation Inhibitors / pharmacokinetics
Platelet Aggregation Inhibitors / pharmacology*
Pyridines / administration & dosage
Pyridines / chemical synthesis
Pyridines / pharmacokinetics
Pyridines / pharmacology*
Rats, Wistar
Receptor, PAR-1 / antagonists & inhibitors*
Structure-Activity Relationship

Substances

5-(2-(5-(3-fluorophenyl)pyridin-2-yl)vinyl)-1,1,4a,6-tetramethyldecahydronaphthalen-2-ol
Diterpenes
Naphthalenes
Platelet Aggregation Inhibitors
Pyridines
Receptor, PAR-1
andrographolide