ABSTRACT
Synthesis of trans-fused lactones containing the indane nucleus has resulted in a series of potent acylating inhibitors of thrombin. As an example compound 11e has an apparent second order rate constant of 11 x 10(6) M(-1)sec(-1) for the inhibition of thrombin. The anticoagulant activity of these compounds is discussed.
Subject(s)
Antithrombins/pharmacology , Indans/chemistry , Lactones/pharmacology , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombins/chemical synthesis , Antithrombins/chemistry , Humans , Kinetics , Lactones/chemical synthesis , Lactones/chemistry , Partial Thromboplastin TimeABSTRACT
Synthesis of a variety of 5,5-trans fused lactones, related to compounds found in extracts of Lantana camara, has provided a series of novel acylating inhibitors of human thrombin, trypsin, chymotrypsin and human leucocyte elastase. The most effective thrombin inhibitor is 7 with an IC50 of 130 nM and a Kobs/[1] of 4,000 M-1 s-1.
Subject(s)
Lactones/chemical synthesis , Serine Proteinase Inhibitors/chemical synthesis , Thrombin/antagonists & inhibitors , Binding Sites , Humans , Kinetics , Serine Proteinase Inhibitors/pharmacologyABSTRACT
A series of trans-fused lactams containing the indane nucleus has been prepared. Compound 19 has much enhanced plasma stability compared with its lactone counterpart and shows appreciable in vitro anticoagulant activity.