Design, synthesis and structure-activity relationship of oxazolidinone derivatives containing novel S4 ligand as FXa inhibitors.
A novel series of potent and efficacious factor Xa inhibitors which possesses pyrrole/indole/thiazole moieties as S4 binding element was identified. Compound 7b showed strong human factor Xa inhibitory activity (IC50 = 2.01 nM) and anticoagulant activities in both human (PTCT2 = 0.15 μM, APPTCT2 = 0.30 μM) and rabbit plasma (PTCT2 = 0.46 μM, APPTCT2 = 0.75 μM). The SARs analyses indicated that the size and water solubility of different alkylamino group at the position of S4 ligand were responsible for the anticoagulant activity.
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Yanfang
Y
Zhao
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Mingyan
M
Jiang
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Shunguang
S
Zhou
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Shasha
S
Wu
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Xiaolong
X
Zhang
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Longsheng
L
Ma
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
Kai
K
Zhang
Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: gongpinggp@126.com.
Ping
P
Gong
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D015951:Factor Xa / Q000378:metabolism*; D065427:Factor Xa Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D008024:Ligands; D010080:Oxazoles; C064210:oxazolidine; D015951:Factor Xa
Anticoagulant activity; Factor Xa inhibitors; Oxazolidinone derivatives; Synthesis