ABSTRACT
Here we report the discovery and optimization of a series of bivalent bromodomain and extraterminal inhibitors. Starting with the observation of BRD4 activity of compounds from a previous program, the compounds were optimized for BRD4 potency and physical properties. The optimized compound from this campaign exhibited excellent pharmacokinetic profile and exhibited high potency in vitro and in vivo effecting c-Myc downregulation and tumor growth inhibition in xenograft studies. This compound was selected as the development candidate, AZD5153. The series showed enhanced potency as a result of bivalent binding and a clear correlation between BRD4 activity and cellular potency.
Subject(s)
Antineoplastic Agents/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Nuclear Proteins/antagonists & inhibitors , Piperazines/chemistry , Transcription Factors/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Caco-2 Cells , Cell Cycle Proteins , Crystallography, X-Ray , Dogs , Female , Hepatocytes/drug effects , Hepatocytes/metabolism , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/pharmacology , Heterografts , Humans , Mice, SCID , Neoplasm Transplantation , Piperazines/pharmacokinetics , Piperazines/pharmacology , Protein Conformation , Pyrazoles , Pyridazines , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.
Subject(s)
Antineoplastic Agents/metabolism , Cinnamates/chemistry , Cinnamates/metabolism , Estrogen Antagonists/chemical synthesis , Estrogen Antagonists/pharmacology , Estrogen Receptor Modulators/chemical synthesis , Estrogen Receptor Modulators/pharmacology , Indoles/chemistry , Indoles/metabolism , Antineoplastic Agents/chemistry , Breast Neoplasms/drug therapy , Cell Line, Tumor , Cell Proliferation/drug effects , Clinical Trials, Phase I as Topic , Down-Regulation/drug effects , Drug Design , Female , Humans , Injections, Intramuscular , X-Ray DiffractionABSTRACT
Two structurally distinct series of novel, MAPK-activated kinase-2 prevention of activation inhibitors have been discovered by high throughput screening. Preliminary structure-activity relationship (SAR) studies revealed substructural features that influence the selective inhibition of the activation by p38α of the downstream kinase MK2 in preference to an alternative substrate, MSK1. Enzyme kinetics, surface plasmon resonance (SPR), 2D protein NMR, and X-ray crystallography were used to determine the binding mode and the molecular mechanism of action. The compounds bind competitively to the ATP binding site of p38α but unexpectedly with higher affinity in the p38α-MK2 complex compared with p38α alone. This observation is hypothesized to be the origin of the substrate selectivity. The two lead series identified are suitable for further investigation for their potential to treat chronic inflammatory diseases with improved tolerability over previously studied p38α inhibitors.
Subject(s)
MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding, Competitive , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Discovery , Enzyme Activation/drug effects , Humans , Kinetics , MAP Kinase Kinase 2/metabolism , Magnetic Resonance Spectroscopy , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Mitogen-Activated Protein Kinase 14/chemistry , Mitogen-Activated Protein Kinase 14/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Phosphorylation/drug effects , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Ribosomal Protein S6 Kinases, 90-kDa/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 90-kDa/chemistry , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Structure-Activity Relationship , Substrate Specificity , Surface Plasmon ResonanceABSTRACT
Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.
Subject(s)
Acrylamides/pharmacology , Aniline Compounds/pharmacology , Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Carcinoma, Non-Small-Cell Lung/genetics , Chemistry Techniques, Synthetic , Drug Resistance, Neoplasm/drug effects , ErbB Receptors/genetics , Female , Humans , Inhibitory Concentration 50 , Lung Neoplasms/genetics , Male , Mice , Middle Aged , Mutation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Rats, Inbred Strains , Xenograft Model Antitumor AssaysABSTRACT
Aziridines formed upon treatment of allylic carbamates and homoallylic sulfamates with Rh(II) carboxylate catalysts under oxidative conditions are trapped by suitably-disposed hydroxyl groups to give functionalised tetrahydrofurans.
Subject(s)
Aziridines/chemistry , Furans/chemical synthesis , Rhodium/chemistry , Alkenes/chemistry , Catalysis , Hydroxyl Radical/chemistry , Stereoisomerism , X-Ray DiffractionABSTRACT
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
Subject(s)
Down-Regulation/drug effects , Drug Discovery , Prostatic Neoplasms/drug therapy , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Small Molecule Libraries/pharmacology , Animals , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Molecular Structure , Prostatic Neoplasms/pathology , Pyridazines/chemical synthesis , Pyridazines/chemistry , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity RelationshipABSTRACT
We describe a concise synthesis of (+)-isoaltholactone via a Au-catalysed cyclisation of a monoallylic diol to form the tetrahydrofuranyl ring. Analogous cyclisations show that the stereochemical outcome is dictated by the stereochemistry of the diol substrate.
Subject(s)
Furans/chemical synthesis , Gold/chemistry , Pyrones/chemical synthesis , Catalysis , Cyclization , Furans/chemistry , Pyrones/chemistry , StereoisomerismABSTRACT
A novel method is presented using N-N ylides (prepared by in situ amination of a tertiary amine) for the aziridination of a range of enone systems. The amine may be used sub-stoichiometrically, and promising levels of enantioselectivity are observed with quinine as promoter. [reaction: see text].
