Subject(s)
Drug Discovery , Receptors, Metabotropic Glutamate/metabolism , Receptors, Muscarinic/metabolism , Small Molecule Libraries/chemistry , Allosteric Regulation , Allosteric Site , Drug Design , Humans , Ligands , Protein Multimerization , Receptors, Metabotropic Glutamate/chemistry , Receptors, Muscarinic/chemistry , Small Molecule Libraries/chemical synthesis , Structure-Activity RelationshipABSTRACT
Chemical strategies to mitigate cytochrome P450-mediated bioactivation of novel 2,7-disubstituted pyrrolo[2,1-f][1,2,4]triazine ALK inhibitors are described along with synthesis and biological activity. Piperidine-derived analogues showing minimal microsomal reactive metabolite formation were discovered. Potent, selective, and metabolically stable ALK inhibitors from this class were identified, and an orally bioavailable compound (32) with antitumor efficacy in ALK-driven xenografts in mouse models was extensively characterized.
Subject(s)
Aniline Compounds/chemical synthesis , Antineoplastic Agents/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazines/chemical synthesis , Administration, Oral , Anaplastic Lymphoma Kinase , Aniline Compounds/pharmacokinetics , Aniline Compounds/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Biological Availability , In Vitro Techniques , Mice , Mice, SCID , Microsomes, Liver/metabolism , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Triazines/pharmacokinetics , Triazines/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The JAK2/STAT pathway has important roles in hematopoiesis. With the discovery of the JAK2 V617F mutation and its presence in many patients with myeloproliferative neoplasms, research in the JAK2 inhibitor arena has dramatically increased. We report a novel series of potent JAK2 inhibitors containing a 2,7-pyrrolotriazine core. To minimize potential drug-induced toxicity, targets were analyzed for the ability to form a glutathione adduct. Glutathione adduct formation was decreased by modification of the aniline substituent at C2.
Subject(s)
Janus Kinase 2/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyrroles/chemistry , Triazines/metabolism , Amino Acid Substitution , Glutathione/chemistry , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Myeloproliferative Disorders/metabolism , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Triazines/chemistryABSTRACT
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
Subject(s)
Chemistry, Pharmaceutical , Glutathione/metabolism , Microsomes, Liver/enzymology , Protein Kinase Inhibitors/metabolism , Pyrroles/metabolism , Triazines/metabolism , Animals , Bile/chemistry , Biotransformation , Chromans/metabolism , Chromatography, High Pressure Liquid , Chromatography, Liquid , Clozapine/metabolism , Dogs , Haplorhini , Humans , Mice , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/urine , Protein Kinases/metabolism , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Pyrroles/urine , Rats , Spectrometry, Mass, Electrospray Ionization , Sulfhydryl Compounds/metabolism , Thiazolidinediones/metabolism , Triazines/chemical synthesis , Triazines/pharmacokinetics , Triazines/urine , TroglitazoneABSTRACT
A novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine scaffold has been designed as a new kinase inhibitor platform mimicking the bioactive conformation of the well-known diaminopyrimidine motif. The design, synthesis, and validation of this new pyrrolo[2,1-f][1,2,4]triazine scaffold will be described for inhibitors of anaplastic lymphoma kinase (ALK). Importantly, incorporation of appropriate potency and selectivity determinants has led to the discovery of several advanced leads that were orally efficacious in animal models of anaplastic large cell lymphoma (ALCL). A lead inhibitor (30) displaying superior efficacy was identified and in depth in vitro/in vivo characterization will be presented.
Subject(s)
Antineoplastic Agents/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Pyrroles/chemical synthesis , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Sulfonamides/chemical synthesis , Triazines/chemical synthesis , Anaplastic Lymphoma Kinase , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cell Line, Tumor , Cell Membrane Permeability , Drug Screening Assays, Antitumor , Humans , In Vitro Techniques , Lymphoma, Large-Cell, Anaplastic/drug therapy , Mice , Mice, SCID , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacology , Transplantation, Heterologous , Triazines/pharmacokinetics , Triazines/pharmacologyABSTRACT
A series of novel pyrrolocarbazole lactams was identified as potent PARP-1 inhibitors in vitro and in a PC12 cellular NAD(+) depletion assay. The SAR trends of substituents at the 3-position, as well as the effect of blocking the indole or lactam NH-groups of the template by methylation or formylation, are discussed in relation to molecular modeling studies.
Subject(s)
Carbazoles/chemistry , Carbazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Lactams/chemistry , Lactams/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Carbazoles/chemical synthesis , Cell Membrane Permeability/drug effects , Enzyme Inhibitors/chemistry , Imides/chemistry , Inhibitory Concentration 50 , Lactams/chemical synthesis , Models, Molecular , PC12 Cells , Poly(ADP-ribose) Polymerases/chemistry , Poly(ADP-ribose) Polymerases/metabolism , Protein Structure, Tertiary , Pyrroles/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.
Subject(s)
Carbazoles/chemical synthesis , Carbazoles/pharmacology , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors , Carbazoles/chemistry , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Structure , Poly (ADP-Ribose) Polymerase-1 , Structure-Activity RelationshipABSTRACT
A series of potent 1,2-benzothiazine 1,1-dioxide alpha-ketoamide inhibitors of calpain I is described.