Contemporary developments in the discovery of selective factor Xa inhibitors: A review

• Published in: European journal of medicinal chemistry 2016-10, Vol.121, p.671-698
• Main Authors: Patel, Nirav R., Patel, Dushyant V., Murumkar, Prashant R., Yadav, Mange Ram
• Format: Article
• Language: English
• Subjects: Drug Discovery - methods; Factor Xa; Factor Xa Inhibitors - chemistry; Factor Xa Inhibitors - pharmacology; FXa inhibitors; Humans; Organic Chemicals - chemistry; Organic Chemicals - pharmacology; Structure-Activity Relationship; Thrombosis
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.05.039

Thrombosis is a leading cause of death in cardiovascular diseases such as myocardial infarction (MI), unstable angina and acute coronary syndrome (ACS) in the industrialized world. Venous thromboembolism is observed in about 1 million people every year in United States causing significant morbidity and mortality. Conventional antithrombotic therapy has been reported to have several disadvantages and limitations like inconvenience in oral administration, bleeding risks (heparin analogs), narrow therapeutic window and undesirable interactions with food and drugs (vitamin K antagonist-warfarin). The unmet medical demand for orally active safe anticoagulants has generated widespread interest among the medicinal chemists engaged in this field. To modulate blood coagulation, various enzymes involved in the coagulation process have received great attention as potential targets by various research groups for the development of oral anticoagulants. Among these enzymes, factor Xa (FXa) has remained the centre of attention in the last decade. Intensive research efforts have been made by various research groups for the development of small, safe and orally bioavailable FXa inhibitors. This review is an attempt to compile the research work of various researchers in the direction of development of FXa inhibitors reported since 2010 onward. [Display omitted] •The review describes the current developments for the discovery of FXa inhibitors.•Structural requirements for the inhibition of FXa on the basis of active site of the enzyme have been discussed.•Various strategies adopted for the development of FXa inhibitors on the basis of their chemical classes have been discussed systematically.•Development of selective FXa inhibitors for the treatment of thrombosis is preferred over non-selective inhibitors.