ABSTRACT
Derivatives of lactam, cyclic urea and carbamate were explored as aniline amide replacements in a series of phthalazinone-based ROCK inhibitors. Potent ROCK2 inhibitors such as 22 were identified with excellent overall kinase selectivity as well as good isoform selectivity over ROCK1.
Subject(s)
Amides , Lactams , rho-Associated Kinases , Lactams/pharmacology , Protein Isoforms , rho-Associated Kinases/antagonists & inhibitorsABSTRACT
Structure-activity relationship optimization on a series of phenylpyrazole amides led to the identification of a dual ROCK1 and ROCK2 inhibitor (25) which demonstrated good potency, kinome selectivity and favorable pharmacokinetic profiles. Compound 25 was selected as a tool molecule for in vivo studies including evaluating hemodynamic effects in telemeterized mice, from which moderate decreases in blood pressure were observed.
Subject(s)
Amides/pharmacology , Drug Discovery , Protein Kinase Inhibitors/pharmacology , Pyrazoles/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Blood Pressure/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
A novel series of 5H-chromeno[3,4-c]pyridine, 6H-isochromeno[3,4-c]pyridine and 6H-isochromeno[4,3-d]pyrimidine derivatives as dual ROCK1 and ROCK2 inhibitors is described. Optimization led to compounds with sub-nanomolar inhibitory affinity for both kinases and excellent kinome selectivity. Compound 19 exhibited ROCK1 and ROCK2 IC50 of 0.67 nM and 0.18 nM respectively.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , rho-Associated Kinases/antagonists & inhibitors , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Structure-Activity Relationship , rho-Associated Kinases/metabolismABSTRACT
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
Pyridazine and pyridazinone derivatives were designed and synthesized as coagulation factor XIa inhibitors. Potent and selective inhibitors with single digit nanomolar affinity for factor XIa were discovered. Selected inhibitors demonstrated moderate oral bioavailability.
Subject(s)
Factor XIa/antagonists & inhibitors , Pyridazines/pharmacology , Serine Proteinase Inhibitors/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Factor XIa/metabolism , Humans , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Pyridazines/chemical synthesis , Pyridazines/chemistry , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50=2.8µM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).
Subject(s)
Anilides/pharmacology , Factor XIa/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Anilides/chemical synthesis , Animals , Crystallography, X-Ray , Dogs , Phenylalanine/chemical synthesis , Rabbits , Structure-Activity RelationshipABSTRACT
Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 µM. Dose-dependent efficacy (EC50 of 0.53 µM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.
ABSTRACT
To selectively target doxorubicin (Dox) to tumor tissue and thereby improve the therapeutic index and/or efficacy of Dox, matrix metalloproteinases (MMP) activated peptide-Dox prodrugs were designed and synthesized by coupling MMP-cleavable peptides to Dox. Preferred conjugates were good substrates for MMPs, poor substrates for neprilysin, an off-target proteinase, and stable in blood ex vivo. When administered to mice with HT1080 xenografts, conjugates, such as 19, preferentially released Dox in tumor relative to heart tissue and prevented tumor growth with less marrow toxicity than Dox.
Subject(s)
Antineoplastic Agents/chemistry , Doxorubicin/analogs & derivatives , Drug Discovery , Matrix Metalloproteinases/chemistry , Prodrugs/chemistry , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Doxorubicin/pharmacology , Drug Discovery/methods , Humans , Matrix Metalloproteinases/pharmacology , Mice , Prodrugs/pharmacology , Xenograft Model Antitumor Assays/methodsABSTRACT
Introduction of the phenyl piperidinone and phenyl pyridinone P4 moieties in the anthranilamide scaffold led to potent, selective, and orally bioavailable inhibitors of factor Xa. Anthranilamide 28 displayed comparable efficacy to apixaban in the rabbit arteriovenous-shunt (AV) thrombosis model.
Subject(s)
Antithrombin III , Piperidines/chemistry , Pyridones/chemistry , Serine Proteinase Inhibitors , Thrombosis/drug therapy , ortho-Aminobenzoates/chemistry , Administration, Oral , Animals , Antithrombin III/administration & dosage , Antithrombin III/chemical synthesis , Antithrombin III/pharmacokinetics , Arteriovenous Shunt, Surgical , Binding Sites , Biological Availability , Models, Animal , Rabbits , Serine Proteinase Inhibitors/administration & dosage , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Thrombosis/etiologyABSTRACT
As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties.
Subject(s)
Anticoagulants/pharmacology , Factor Xa Inhibitors , Lactams/pharmacology , Piperidones/pharmacology , Sulfonamides/pharmacology , Anticoagulants/chemical synthesis , Binding Sites , Blood Coagulation Tests , Lactams/chemical synthesis , Ligands , Models, Chemical , Piperidones/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
The design and synthesis of a novel class of amino(methyl) pyrrolidine-based sulfonamides as potent and selective FXa inhibitors is reported. The amino(methyl) pyrrolidine scaffolds were designed based on the proposed bioisosterism to the piperazine core in known FXa inhibitors. The SAR study led to compound 15 as the most potent FXa inhibitor in this series, with an IC(50) of 5.5 nM and PT EC(2x) of 1.7 microM. The proposed binding models show that the pyrrolidine cores are in van der Waals contact with the enzyme surface, and the flexibility of amino(methyl) pyrrolidines allows the two nitrogen atoms to anchor both the P1 and P4 groups to fit similarly in the S1 and S4 pockets.
Subject(s)
Factor Xa Inhibitors , Pyrrolidines/chemistry , Serine Proteinase Inhibitors/pharmacology , Models, Molecular , Serine Proteinase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
The design and synthesis of tetrapeptide-based alpha-ketoamides containing prime side acid isosteres HCV NS3 protease inhibitors are described. Tetrazole, sulfonic acid, and N-sulfonylcarboxamids were demonstrated to be efficient carboxylic acid replacements. Further optimization yielded a series of potent HCV NS3 protease inhibitors with IC(50) of 0.020-0.060 microM.
Subject(s)
Amides/chemical synthesis , Glycine/analogs & derivatives , Hepacivirus/enzymology , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemistry , Amides/pharmacology , Binding Sites , Carboxylic Acids/chemistry , Glycine/chemical synthesis , Glycine/pharmacology , Inhibitory Concentration 50 , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Sulfonic Acids/chemistry , Tetrazoles/chemistryABSTRACT
Using a tetrapeptide-based alpha-ketoamide template, various amines and amino acids were incorporated to explore the prime side of the HCV NS3 protease catalytic site. Glycine carboxylic acid was found to be the most effective prime group. Further optimization yielded an inhibitor with IC(50) of 0.060 microM.