ABSTRACT
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.
Subject(s)
Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Lymphoma, Large B-Cell, Diffuse/drug therapy , Molecular Targeted Therapy , Myeloid Differentiation Factor 88/genetics , Quinazolines/chemistry , Quinazolines/pharmacology , Administration, Oral , Animals , Cell Line, Tumor , Drug Design , Female , Humans , Interleukin-1 Receptor-Associated Kinases/chemistry , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/pathology , Mice , Models, Molecular , Mutation , Protein Conformation , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Quinazolines/administration & dosage , Quinazolines/pharmacokinetics , Rats , Rats, Wistar , Structure-Activity Relationship , Tissue Distribution , Xenograft Model Antitumor AssaysABSTRACT
Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Receptor Antagonists/therapeutic use , Heterocyclic Compounds, 3-Ring/therapeutic use , Indazoles/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacokinetics , Dogs , Drug Screening Assays, Antitumor , Estrogen Receptor Antagonists/chemical synthesis , Estrogen Receptor Antagonists/pharmacokinetics , Estrogen Receptor alpha/metabolism , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , MCF-7 Cells , Male , Mice, SCID , Microsomes, Liver/metabolism , Molecular Structure , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
We have developed a series of orally efficacious IRAK4 inhibitors, based on a scaffold hopping strategy and using rational structure based design. Efforts to tackle low permeability and high efflux in our previously reported pyrrolopyrimidine series (Scott et al., 2017) led to the identification of pyrrolotriazines which contained one less formal hydrogen bond donor and were intrinsically more lipophilic. Further optimisation of substituents on this pyrrolotriazine core culminated with the discovery of 30 as a promising in vivo probe to assess the potential of IRAK4 inhibition for the treatment of MyD88 mutant DLBCL in combination with a BTK inhibitor. When tested in an ABC-DLBCL model with a dual MyD88/CD79 mutation (OCI-LY10), 30 demonstrated tumour regressions in combination with ibrutinib.
Subject(s)
Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Pyrroles/chemistry , Thiazines/chemistry , Animals , Binding Sites , Caco-2 Cells , Dogs , Drug Design , Half-Life , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Interleukin-1 Receptor-Associated Kinases/metabolism , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/pathology , Molecular Dynamics Simulation , Mutation , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Permeability/drug effects , Protein Kinases/chemistry , Protein Kinases/metabolism , Pyrroles/pharmacokinetics , Pyrroles/pharmacology , Rats , Structure-Activity Relationship , Thiazines/pharmacokinetics , Thiazines/pharmacologyABSTRACT
Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
Subject(s)
Antineoplastic Agents/pharmacology , Interleukin-1 Receptor-Associated Kinases/antagonists & inhibitors , Lymphoma, Large B-Cell, Diffuse/drug therapy , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Crystallography, X-Ray , Dogs , Female , Humans , Interleukin-1 Receptor-Associated Kinases/chemistry , Lymphoma, Large B-Cell, Diffuse/genetics , Magnetic Resonance Spectroscopy , Male , Mice, SCID , Mutation , Myeloid Differentiation Factor 88/genetics , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/chemistry , Pyrroles/chemistry , Rats, Wistar , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of tetrahydroisoquinoline phenols was modified to give an estrogen receptor downregulator-antagonist profile. Optimization around the core, alkyl side chain, and pendant aryl ring resulted in compounds with subnanomolar levels of potency. The phenol functionality was shown to be required to achieve highly potent compounds, but unusually this was compatible with obtaining high oral bioavailabilities in rat.
ABSTRACT
A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
Subject(s)
Estrogen Receptor alpha/metabolism , Umbelliferones/chemistry , Umbelliferones/pharmacology , Administration, Oral , Animals , Cell Line, Tumor , Coumarins/chemistry , Coumarins/pharmacokinetics , Coumarins/pharmacology , Down-Regulation/drug effects , Estrogen Receptor alpha/analysis , Humans , Molecular Docking Simulation , Rats , Umbelliferones/pharmacokineticsABSTRACT
4-Alkyl- and 4-H-pyrazoles were sequentially metalated using TMPMgCl·LiCl, and their reaction with electrophiles afforded 3-aryl-4-alkyl-5-cyanopyrazoles.
Subject(s)
Hydrocarbons, Halogenated/chemistry , Magnesium/chemistry , Nitriles/chemical synthesis , Pyrazoles/chemical synthesis , Combinatorial Chemistry Techniques , Molecular Structure , Nitriles/chemistry , Organometallic Compounds/chemistry , Pyrazoles/chemistry , StereoisomerismABSTRACT
The design of compounds that selectively inhibit a single kinase is a significant challenge, particularly for compounds that bind to the ATP site. We describe here how protein-ligand crystal structure information was able both to rationalize observed selectivity and to guide the design of more selective compounds. Inhibition data from enzyme and cellular screens and the crystal structures of a range of ligands tested during the process of identifying selective inhibitors of FGFR provide a step-by-step illustration of the process. Steric effects were exploited by increasing the size of ligands in specific regions in such a way as to be tolerated in the primary target and not in other related kinases. Kinases are an excellent target class to exploit such approaches because of the conserved fold and small side chain mobility of the active form.
Subject(s)
Pyrazoles/chemistry , Pyrimidines/chemistry , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Animals , Binding Sites , Crystallography, X-Ray , Dimerization , Drug Design , Humans , Ligands , Mice , Mice, Knockout , Models, Molecular , Molecular Structure , Phosphorylation , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptor, Fibroblast Growth Factor, Type 1/chemistry , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Structure-Activity RelationshipABSTRACT
Wide-ranging exploration of potential replacements for a quinoline-based inhibitor of activation of AKT kinase led to number of alternative, novel scaffolds with potentially improved potency and physicochemical properties. Examples showed predictable DMPK properties, and one such compound demonstrated pharmacodynamic knockdown of phosphorylation of AKT and downstream biomarkers in vivo and inhibition of tumor growth in a breast cancer xenograft model.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Allosteric Regulation , Animals , Biological Availability , Biomarkers/metabolism , Cell Line, Tumor , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Mice , Mice, Nude , Models, Molecular , Neoplasm Transplantation , Proto-Oncogene Proteins c-akt/metabolism , Pyrazines/chemical synthesis , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyridazines/chemical synthesis , Pyridazines/chemistry , Pyridazines/pharmacology , Pyridines/chemical synthesis , Pyridines/chemistry , Pyridines/pharmacology , Quinazolines/chemical synthesis , Quinazolines/chemistry , Quinazolines/pharmacology , Rats , Structure-Activity Relationship , Transplantation, HeterologousABSTRACT
Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.
Subject(s)
Amides/chemistry , Models, Chemical , Alkylation , Crystallography, X-Ray , Ephedrine/chemistry , Hydroxylation , Kinetics , Magnetic Resonance Spectroscopy , Molecular Conformation , Oxazoles/chemistry , Proline/chemistry , Stereoisomerism , Sulfur/chemistry , ThermodynamicsABSTRACT
An asymmetric synthesis of aza analogues of the ABC ring system of phorbol and related compounds containing the 5-7-6-fused framework of daphnane involved construction of the central seven-membered ring by a regioselective reduction of a chiral imide and cyclization with trifluoromethanesulfonic acid. Subsequent demethylation and oxidative dearomatization of ring C afforded an enantiopure dienone 20 with the same relative and absolute configuration at the 9- and 10-positions of the phorbol skeleton.
Subject(s)
Aza Compounds/chemical synthesis , Diterpenes , Phorbols/chemical synthesis , Terpenes/chemical synthesis , Catalysis , Chemistry, Organic/methods , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
The degree to which the rotations about the C-N and Ar-CO bonds of aromatic amides occur in a concerted manner was investigated by a variety of NMR and kinetic techniques. Otherwise complex kinetic analyses were simplified by exploiting symmetry and asymmetry in the N-substituents of amides. In 2-unsubstituted 1-naphthamides bearing branched N-substituents, most conformational changes about the amide group were by correlated rotation, though uncorrelated Ar-CO rotation also occurred to some extent. In 2-substituted 1-naphthamides, correlated rotation accounted for all of the Ar-CO rotations, though a significant amount of uncorrelated C-N rotation also occurred. Naphthamides bearing branched N-substituents thus turn out to be efficient molecular gears: Compound 12 showed almost no gear slippage.