title: Prolinamide derivatives as thrombin inhibitors for the treatment of thrombin-mediated diseases: a patent evaluation of US2013296245.
abstract: BACKGROUND
  Thrombotic disorders can lead to deep vein thrombosis, myocardial infarction and stroke. Thrombin plays a vital role in cascade reaction of blood coagulation, inhibition of the activity of thrombin can block the formation of thrombus and direct thrombin inhibitor has a prospect to overcome the limitations in application of the traditional anticoagulant drugs.
  
  
  METHODS
  The current patent US2013296245 describes a series of prolinamide derivatives with formula (I) as thrombin inhibitors. These new compounds are defined to be pharmaceutically acceptable salts derived from pharmaceutically acceptable inorganic acid and organic acid, and pharmaceutically acceptable prodrug where N-alkoxycarbonyl is protected or carboxylic acid is protected by ester.
  
  
  CONCLUSIONS
  The patent used formamidine and its N-alkoxycarbonyl-protected derivatives as the P1 group; these groups were less basic compared with the traditional guanidine group, so their lipophilicity could be optimized to achieve oral absorption. Furthermore, these pharmaceutically acceptable prodrugs where N-alkoxycarbonyl is protected or carboxylic acid is protected by ester could achieve prolonged half-life for a convenient once- or twice-daily oral dosing. These efforts gave a new hope and confidence to treat thrombotic disorders with selective and orally active thrombin inhibitors.
authors.affiliation: Nanjing University of Chinese Medicine, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine , 138 Xianlin Road, Nanjing 210023, Jiangsu , PR China +86 25 85811916 ; +86 25 85811916 ; linianguang@njutcm.edu.cn , yupingtang@njutcm.edu.cn.
authors.forename: Zhi-Hao
authors.initials: ZH
authors.lastname: Shi
authors.forename: Nian-Guang
authors.initials: NG
authors.lastname: Li
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Tang
authors.forename: Jin-Ao
authors.initials: JA
authors.lastname: Duan
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000627:therapeutic use*; D006801:Humans; D010330:Patents as Topic; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D000925:Anticoagulants; D011392:Proline; D013917:Thrombin
keywords: inhibitor; prolinamide; pulmonary embolism; thrombin; venous thrombosis