title: Identification of anthranilamide derivatives as potential factor Xa inhibitors: drug design, synthesis and biological evaluation.
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.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: xingjhcpu@163.com.
authors.forename: Junhao
authors.initials: J
authors.lastname: Xing
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Lingyun
authors.initials: L
authors.lastname: Yang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Leilei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Xinning
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Muxing
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Medicinal Chemistry, China Pharmaceutical University, TongjiaXiang 24, 210009 Nanjing, PR China.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Huibin
authors.initials: H
authors.lastname: Zhang
mesh_terms: D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D011517:Prothrombin Time; D013918:Thrombin Time; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D065427:Factor Xa Inhibitors; D062367:ortho-Aminobenzoates; D015951:Factor Xa; C000219:anthranilamide
keywords: Anticoagulant; Consensus docking; FBDD; Factor Xa; Prothrombin time; Structure-based pharmacophore