Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation

Junhao Xing; Lingyun Yang; Hui Li; Qing Li; Leilei Zhao; Xinning Wang; Yuan Zhang; Muxing Zhou; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.ejmech.2015.03.052

Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation

Eur J Med Chem. 2015 May 5:95:388-99. doi: 10.1016/j.ejmech.2015.03.052. Epub 2015 Mar 25.

Authors

Junhao Xing¹, Lingyun Yang², Hui Li², Qing Li², Leilei Zhao², Xinning Wang², Yuan Zhang³, Muxing Zhou², Jinpei Zhou³, Huibin Zhang⁴

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xingjhcpu@163.com.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
⁴ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: hb_zhang@hotmail.com.

PMID: 25839438
DOI: 10.1016/j.ejmech.2015.03.052

Abstract

The coagulation enzyme factor Xa (fXa) plays a crucial role in the blood coagulation cascade. In this study, three-dimensional fragment based drug design (FBDD) combined with structure-based pharmacophore (SBP) model and structural consensus docking were employed to identify novel fXa inhibitors. After a multi-stage virtual screening (VS) workflow, two hit compounds 3780 and 319 having persistent high performance were identified. Then, these two hit compounds and several analogs were synthesized and screened for in-vitro inhibition of fXa. The experimental data showed that most of the designed compounds displayed significant in vitro potency against fXa. Among them, compound 9b displayed the greatest in vitro potency against fXa with the IC50 value of 23 nM and excellent selectivity versus thrombin (IC50 = 40 μM). Moreover, the prolongation of the prothrombin time (PT) was measured for compound 9b to evaluate its in vitro anticoagulant activity. As a result, compound 9b exhibited pronounced anticoagulant activity with the 2 × PT value of 8.7 μM.

Keywords: Anticoagulant; Consensus docking; FBDD; Factor Xa; Prothrombin time; Structure-based pharmacophore.

Publication types

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

MeSH terms

Chemistry Techniques, Synthetic
Drug Design*
Factor Xa / chemistry
Factor Xa / metabolism*
Factor Xa Inhibitors / chemical synthesis*
Factor Xa Inhibitors / chemistry
Factor Xa Inhibitors / metabolism
Factor Xa Inhibitors / pharmacology*
Humans
Molecular Docking Simulation
Protein Conformation
Prothrombin Time
Thrombin Time
ortho-Aminobenzoates / chemical synthesis*
ortho-Aminobenzoates / chemistry
ortho-Aminobenzoates / pharmacology*

Substances

Factor Xa Inhibitors
ortho-Aminobenzoates
Factor Xa
anthranilamide