ABSTRACT
Leukotrienes (LTs) and related species are proinflammatory lipid mediators derived from arachidonic acid (AA) that have pathological roles in autoimmune and inflammatory conditions, cardiovascular diseases, and cancer. 5-Lipoxygenase activating protein (FLAP) plays a critical accessory role in the conversion of AA to LTA4, and its subsequent conversion to LTC4 by LTC4 synthase. Pharmacological inhibition of FLAP results in a loss of LT production by preventing the biosynthesis of both LTB4 and LTC4, making it an attractive target for the treatment of inflammatory diseases in which LTs likely play a role. Small-molecule (SM) drugs often exhibit polypharmacology through various pathways, which may explain the differential therapeutic efficacies of compounds sharing structural similarity. We have profiled a series of SM FLAP modulators for their selectivity across enzymes of AA cascade in human whole blood (HWB), using a recently developed LC/MS (liquid chromatography-mass spectrometry)-based high-throughput lipidomics platform that monitors 122 eicosanoids in multiplex. Highly efficient data acquisition coupled with fast and accurate data analysis allowed facile compound profiling from ex vivo study samples. This platform allowed us to quantitatively map the effects of those SMs on the entire AA cascade, demonstrating its potential to discriminate structurally related compounds.
Subject(s)
5-Lipoxygenase-Activating Proteins/chemistry , Small Molecule Libraries/chemistry , Eicosanoids/chemistry , Glutathione Transferase/chemistry , Humans , Leukotrienes/chemistry , PolypharmacologyABSTRACT
Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.
Subject(s)
Pyridines/pharmacology , Receptors, G-Protein-Coupled/drug effects , Receptors, Histamine/drug effects , Humans , Pyridines/chemistry , Receptors, Histamine H4ABSTRACT
During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.
Subject(s)
Histamine Antagonists/pharmacokinetics , Pyridines/chemistry , Pyrimidines/chemistry , Receptors, G-Protein-Coupled/drug effects , Receptors, Histamine/drug effects , Histamine Antagonists/therapeutic use , Humans , Ligands , Molecular Structure , Receptors, Histamine H4ABSTRACT
This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.
Subject(s)
Histamine Antagonists/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Histamine Antagonists/chemistry , Mice , Receptors, Histamine , Receptors, Histamine H4ABSTRACT
Two series of triamino pyrimidines and a series of triamino pyridines have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. Small structural changes in these three hetereoaromatic cores influenced the functional activity of these compounds.
Subject(s)
Pyridines/pharmacology , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Amines/chemistry , Binding, Competitive , Biological Assay , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptors, Histamine , Receptors, Histamine H4 , Structure-Activity RelationshipABSTRACT
High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).
Subject(s)
Cathepsins/antagonists & inhibitors , Cathepsins/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Aza Compounds/pharmacology , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/pharmacology , Carboxylic Acids/chemical synthesis , Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Humans , Indoles/chemical synthesis , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , Protease Inhibitors/chemistry , Pyrazoles/chemical synthesis , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/chemistry , Thiophenes/pharmacologyABSTRACT
A series of oxamyl dipeptides were optimized for pan caspase inhibition, anti-apoptotic cellular activity and in vivo efficacy. This structure-activity relationship study focused on the P4 oxamides and warhead moieties. Primarily on the basis of in vitro data, inhibitors were selected for study in a murine model of alpha-Fas-induced liver injury. IDN-6556 (1) was further profiled in additional in vivo models and pharmacokinetic studies. This first-in-class caspase inhibitor is now the subject of two Phase II clinical trials, evaluating its safety and efficacy for use in liver disease.
Subject(s)
Caspase Inhibitors , Liver Diseases/drug therapy , Pentanoic Acids/chemical synthesis , Adult , Alanine Transaminase/blood , Animals , Apoptosis/drug effects , Aspartate Aminotransferases/blood , Biological Availability , Caspase 3 , Cholestasis/drug therapy , Cholestasis/pathology , Clinical Trials, Phase I as Topic , Half-Life , Hepatitis C, Chronic/drug therapy , Hepatocytes/drug effects , Hepatocytes/pathology , Humans , Jurkat Cells , Liver/drug effects , Liver/pathology , Liver Diseases/enzymology , Liver Diseases/etiology , Mice , Pentanoic Acids/chemistry , Pentanoic Acids/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Various heterocyclic hetero-methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A study of their structure-activity relationship (SAR) related to caspase-1, -3, -6, and -8 is reported. Their efficacy in a cellular model of cell death is also discussed. Potent broad-spectrum caspase inhibitors have been identified.
Subject(s)
Caspase Inhibitors , Cell Death/drug effects , Cysteine Proteinase Inhibitors/pharmacology , Heterocyclic Compounds/pharmacology , Ketones/pharmacology , Animals , Aspartic Acid/chemistry , Cells, Cultured , Heterocyclic Compounds/chemical synthesis , Ketones/chemical synthesis , Mice , Models, Biological , Naphthols/chemistry , Structure-Activity Relationship , Valine/chemistryABSTRACT
A novel series of competitive, reversible cathepsin S (CatS) inhibitors was discovered and optimized. The 4-(2-keto-1-benzimidazolinyl)-piperidin-1-yl moiety was found to be an effective replacement for the 4-arylpiperazin-1-yl group found in our earlier series of CatS inhibitors. This replacement imparted improved PK properties as well as decreased off-target activity. Optimization of the ketobenzimidazole moiety led to the discovery of the lead compound JNJ 10329670, which represents a novel class of selective, noncovalent, reversible, and orally bioavailable inhibitors of cathepsin S.
Subject(s)
Cathepsins/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Cell Line , Heterocyclic Compounds, 2-Ring/chemistry , Heterocyclic Compounds, 2-Ring/pharmacology , Models, Chemical , Molecular Structure , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/chemistry , Pyridines/pharmacokinetics , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
The first nonpeptidic, noncovalent inhibitors of the cysteine protease cathepsin S (CatS) are described. Electronic database searching using the program DOCK generated a screening set of potential CatS inhibitors from which two lead structures were identified as promising starting points for a drug discovery effort. Lead optimization afforded potent (IC(50) < 50 nM) and selective inhibitors of CatS demonstrating cellular activity and reversibility of enzyme inhibition.
Subject(s)
Cathepsins/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , B-Lymphocytes/drug effects , B-Lymphocytes/metabolism , Cathepsins/chemistry , Cells, Cultured , Drug Evaluation, Preclinical/methods , Histocompatibility Antigens Class II/drug effects , Histocompatibility Antigens Class II/metabolism , Humans , Immunoglobulin Constant Regions/drug effects , Immunoglobulin Constant Regions/metabolism , Inhibitory Concentration 50 , Peptides/chemistry , Peptides/pharmacology , Protein Conformation , Structure-Activity RelationshipABSTRACT
Structural modifications were made to a previously described acyl dipeptide caspase inhibitor, leading to the oxamyl dipeptide series. Subsequent SAR studies directed toward the warhead, P2, and P4 regions of this novel peptidomimetic are described herein.
Subject(s)
Caspase Inhibitors , Dipeptides/chemical synthesis , Dipeptides/pharmacology , Apoptosis/drug effects , Carbamates , Cell Line , Humans , Inhibitory Concentration 50 , Kinetics , Neurodegenerative Diseases/drug therapy , Stroke/drug therapy , Structure-Activity RelationshipABSTRACT
Various aryloxy methyl ketones of the 1-naphthyloxyacetyl-Val-Asp backbone have been prepared. A systematic study of their structure-activity relationship (SAR) related to caspases 1, 3, 6, and 8 is reported. Highly potent irreversible broad-spectrum caspase inhibitors have been identified. Their efficacy in cellular models of cell death and inflammation are also discussed.
Subject(s)
Caspase Inhibitors , Cysteine Proteinase Inhibitors/chemistry , Cysteine Proteinase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A new structural class of broad spectrum caspase inhibitors was optimized for its activity against caspases 1, 3, 6, 7, and 8. The most potent compound had low nanomolar broad spectrum activity, in particular, single digit nanomolar inhibitory activity against caspase 8.
