ABSTRACT
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa Ki = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.
Subject(s)
Carotid Artery Thrombosis , Factor XIa , Fibrinolytic Agents , Pyrimidines , Triazoles , Animals , Mice , Rabbits , Administration, Oral , Carotid Artery Thrombosis/drug therapy , Factor XIa/antagonists & inhibitors , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Fibrinolytic Agents/therapeutic use , Macaca fascicularis , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemical synthesis , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyrimidines/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazoles/administration & dosage , Triazoles/chemical synthesis , Triazoles/pharmacokinetics , Triazoles/therapeutic useABSTRACT
This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.
Subject(s)
Drug Design , Drug Discovery , Factor XIa/antagonists & inhibitors , Macrocyclic Compounds/administration & dosage , Macrocyclic Compounds/chemistry , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemistry , Administration, Oral , Biological Availability , Humans , Ligands , Macrocyclic Compounds/pharmacology , Models, Molecular , Molecular Structure , Serine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A 6-amidinotetrahydroquinoline screening hit was driven to a structurally novel, potent, and selective FVIIa inhibitor through a combination of library synthesis and rational design. An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial thrombosis model. A crystal structure of BMS-593214 bound to FVIIa highlights key contacts with Asp 189, Lys 192, and the S2 pocket.
Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Factor VIIa/antagonists & inhibitors , Factor VIIa/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Thrombosis/prevention & control , Animals , Benzoates/chemical synthesis , Disease Models, Animal , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Rabbits , Structure-Activity RelationshipABSTRACT
A series of peptide boronic acids containing extended, hydrophobic P1 residues was prepared to probe the shallow, hydrophobic S1 region of HCV NS3 protease. The p-trifluoromethylphenethyl P1 substituent was identified as optimal with respect to inhibitor potency for NS3 and selectivity against elastase and chymotrypsin.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Boronic Acids/chemical synthesis , Boronic Acids/pharmacology , Hepacivirus/enzymology , Peptides/chemical synthesis , Peptides/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Chymotrypsin/antagonists & inhibitors , Hepacivirus/drug effects , Humans , Indicators and Reagents , Leukocytes/drug effects , Leukocytes/enzymology , Pancreas/enzymology , Pancreatic Elastase/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
By passing wild type bovine viral diarrhoea virus (BVDV) in increasing concentrations of DPC-A69280-29, a thiazole urea class compound that inhibits BVDV replication, we were able to select several variants of BVDV that exhibited decreased susceptibility to this compound. When the non-structural genes of these variants were sequenced and compared with wild type, only one change was common to all the variants that also exhibited resistance to DPC-A69280-29 (>10-fold increase in IC50). This change was a T-to-A transversion at position 11198 of the BVDV genome, which would cause a predicted substitution of isoleucine for phenylalanine at amino acid 78 of the RNA-dependent RNA polymerase (RdRp). This substitution would occur in a region of the BVDV RdRp which has been proposed to be important for the formation of the RdRp homodimer that is essential for the activity of the enzyme. However, since DPC-69280-29 inhibits BVDV replication by interfering with the initiation of viral RNA synthesis, we discuss the possibility that this region of the BVDV RdRp also may play a role in the initiation process. Furthermore, since this region is located fairly close to the template RNA, we also propose that the role it plays may involve either template selection, stabilization or processivity.
