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
HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.
Subject(s)
Indoles/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , 3-Phosphoinositide-Dependent Protein Kinases , Drug Design , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesisABSTRACT
High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.
Subject(s)
Anti-HIV Agents/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , CCR5 Receptor Antagonists , Mitoguazone/analogs & derivatives , Anti-HIV Agents/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Structure-Activity RelationshipABSTRACT
The activated Factor VII/tissue factor complex (FVIIa/TF) plays a key role in the formation of blood clots. Inhibition of this complex may lead to new antithrombotic drugs. An X-ray crystal structure of a fluoropyridine-based FVIIa/TF inhibitor bound in the active site of the enzyme complex suggested that incorporation of substitution at the 5-position of the hydroxybenzoic acid side chain could lead to the formation of more potent inhibitors through interactions with the S1'/S2' pocket.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Factor VIIa/chemistry , Fibrinolytic Agents/chemical synthesis , Pyridines/chemical synthesis , Thromboplastin/chemistry , Binding Sites , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Factor VIIa/antagonists & inhibitors , Factor Xa Inhibitors , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Inhibitory Concentration 50 , Protein Binding , Prothrombin Time , Pyridines/chemistry , Structure-Activity Relationship , Thromboplastin/antagonists & inhibitorsABSTRACT
Reductive amination followed by acylation of polymer-linked formyl aryl amidines generate combinatorial libraries of aryl amidines 8-13. Potent small molecule naphthylamidine inhibitors 12 (Ki<100 nM) of FVIIa/TF have been discovered and their activity against other serine proteases in the coagulation cascade is reported.
Subject(s)
Amidines/chemical synthesis , Factor VIIa/antagonists & inhibitors , Thromboplastin/antagonists & inhibitors , Amidines/chemistry , Amidines/pharmacology , Binding Sites , Humans , Kinetics , Models, Molecular , Molecular Conformation , Naphthols/chemical synthesis , Naphthols/chemistry , Naphthols/pharmacology , 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.
Subject(s)
Factor Xa Inhibitors , Thiophenes/pharmacology , ortho-Aminobenzoates/pharmacology , Animals , Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Cattle , Heterocyclic Compounds/pharmacology , Humans , Indicators and Reagents , Kinetics , Prothrombin Time , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship , Thiophenes/chemistry , Thrombin/antagonists & inhibitors , Trypsin Inhibitors/chemical synthesis , Trypsin Inhibitors/pharmacology , ortho-Aminobenzoates/chemistryABSTRACT
A novel potent and selective aminophenol scaffold for fXa inhibitors was developed from a previously reported benzimidazole-based naphthylamidine template. The aminophenol template is more synthetically accessible than the benzimidazole template, which simplified the introduction of carboxylic acid groups. Substitution of a propenyl-para-hydroxy-benzamidine group on the aminophenol template produced selective, sub-nanomolar fXa inhibitors. The potency of the inhibitors is partially explained with the aid of a trypsin complex crystal structure.
