ABSTRACT
There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.
Subject(s)
Amides/chemical synthesis , Aminopyridines/chemical synthesis , Anticoagulants/chemical synthesis , Factor Xa Inhibitors , Thiophenes/chemical synthesis , ortho-Aminobenzoates/chemical synthesis , Amides/pharmacokinetics , Amides/pharmacology , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Animals , Anticoagulants/pharmacokinetics , Anticoagulants/pharmacology , Crystallography, X-Ray , Dogs , Humans , In Vitro Techniques , Male , Models, Molecular , Prothrombin Time , Rats , Rats, Wistar , Structure-Activity Relationship , Thiophenes/pharmacokinetics , Thiophenes/pharmacology , Venous Thrombosis/drug therapy , ortho-Aminobenzoates/pharmacokinetics , ortho-Aminobenzoates/pharmacologyABSTRACT
A series of thiophene-containing non-amidine factor Xa inhibitors is described. Simple methyl-substituted thiophene analogs were relatively weak inhibitors. However, introduction of hydrophilic substituents at C-4 or C-5 of the thiophene afforded inhibitors with low nanomolar potency. Optimization of the thiophene substituent at C-4 afforded subnanomolar inhibitors with improved in vitro anticoagulant activity. Incorporating basic amine substituents on the thiophene increased hydrophilicity and improved anticoagulant activity. The pharmacokinetic profile of one inhibitor was evaluated in dogs, and the X-ray crystal structure of this compound bound to factor Xa provides insight into the observed SAR for binding to factor Xa.
Subject(s)
Amides/pharmacology , Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Thiophenes/chemistry , Amides/chemistry , Animals , Crystallography, X-Ray , Dogs , Humans , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity RelationshipABSTRACT
Compound 2 was identified by high throughput screening as a novel PAI-1 inhibitor. Systematic optimization of the A, B, and C segments of 2 resulted in the identification of a more potent compound 39 with good oral bioavailability. The synthesis and SAR data are presented in this report.
Subject(s)
Piperazines/chemical synthesis , Piperazines/pharmacology , Plasminogen Activator Inhibitor 1/chemistry , Animals , Blood Coagulation Tests , Drug Evaluation, Preclinical , Fibrinolysis/drug effects , Molecular Structure , Plasminogen Activator Inhibitor 1/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Compound 1 was identified by high throughput screening as a novel, potent, non-amidine factor Xa inhibitor with good selectivity against thrombin and trypsin. A series of modifications of the three aromatic groups of 1 was investigated. Substitution of chlorine or bromine for fluorine on the aniline ring led to the discovery of subnanomolar factor Xa inhibitors. Positions on the anthranilic acid ring that can accommodate further substitution were also identified.
