ABSTRACT
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
A modular and scalable approach to pyrimidine- and purine-containing constrained ethyl (cEt) nucleosides is demonstrated. Minimizing stereochemical adjustments and protecting group manipulations, diacetone glucose is converted to two representative cEt nucleosides via a functionalized, common intermediate. The retrosynthetic approach to this complex class of drug precursors offers clear benefits over existing routes based on step count and efficiency.
Subject(s)
Nucleosides/chemical synthesis , Prodrugs/chemical synthesis , Purine Nucleosides/chemical synthesis , Pyrimidine Nucleosides/chemical synthesis , Molecular Structure , Nucleosides/chemistry , Prodrugs/chemistry , Purine Nucleosides/chemistry , Pyrimidine Nucleosides/chemistryABSTRACT
Sulfonyl-derived functional groups populate a broad range of useful molecules and materials, and despite a variety of preparative methods being available, processes which introduce the most basic sulfonyl building block, sulfur dioxide, using catalytic methods, are rare. Described herein is a simple reaction system consisting of the sulfur dioxide surrogate DABSO, triethylamine, and a palladium(0) catalyst for effective convertion of a broad range of aryl and heteroaryl halides into the corresponding ammonium sulfinates. Key features of this gas- and reductant-free reaction include the low loadings of palladium (1â mol%) and ligand (1.5â mol%) which can be employed, and the use of isopropyl alcohol as both a solvent and formal reductant. The ammonium sulfinate products are converted in situ into a variety of sulfonyl-containing functional groups, including sulfones, sulfonyl chlorides, and sulfonamides.
Subject(s)
Hydrocarbons, Halogenated/chemistry , Organometallic Compounds/chemistry , Palladium/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Sulfinic Acids/chemical synthesis , Sulfur Dioxide/chemistry , Catalysis , Molecular Structure , Quaternary Ammonium Compounds/chemistry , Sulfinic Acids/chemistryABSTRACT
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
By using DABCO·(SO(2))(2), DABSO, as a solid bench-stable SO(2)-equivalent, the palladium-catalysed aminosulfonylation of aryl-, alkenyl- and heteroaryl halides has been achieved. N,N-Dialkylhydrazines are employed as the N-nucleophiles and provide N-aminosulfonamides as the products in good to excellent yields. The reactions are operationally simple to perform, requiring only a slight excess of SO(2) (1.2-2.2 equiv.), and tolerate a variety of substituents on the halide coupling partner. Variation of the hydrazine component is also demonstrated. The use of N,N-dibenzylhydrazine as the N-nucleophile delivers N-aminosulfonamide products that can be converted into the corresponding primary sulfonamides using a high-yielding, telescoped, deprotection sequence. The ability to employ hydrazine·SO(2) complexes as both the N-nucleophile and SO(2) source is also illustrated.
Subject(s)
Alkenes/chemistry , Halogens/chemistry , Palladium/chemistry , Sulfonic Acids/chemistry , Catalysis , Molecular StructureABSTRACT
The SAR and improvement in potency against Tie2 of novel thienopyrimidine and thiazolopyrimidine kinase inhibitors are reported. The crystal structure of one of these compounds bound to the Tie-2 kinase domain is consistent with the SAR. These compounds have moderate potency in cellular assays of Tie-2 inhibition, good physical properties, DMPK, and show evidence of in vivo inhibition of Tie-2.
Subject(s)
Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Thiazoles/pharmacology , Crystallography, X-Ray , Drug Design , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
The synthesis of a triglycosylated helical foldamer based on a combination of cyclopentyl- and pyrrolidinyl-based amino acids is described. This structure is stable in water, maintaining as it does a series of carbohydrate units in proximity to one another, and represents the basis of a new approach to the study of carbohydrate-carbohydrate interactions.
Subject(s)
Carbohydrates/chemistry , Peptides/chemistry , Glycosylation , Models, Molecular , Molecular Structure , Protein FoldingABSTRACT
The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.
Subject(s)
Enzyme Activators/chemical synthesis , Glucokinase/metabolism , Animals , Drug Evaluation, Preclinical/methods , Enzyme Activation/physiology , Enzyme Activators/pharmacology , Female , Rats , Rats, Wistar , Thiazoles/chemical synthesis , Thiazoles/pharmacologyABSTRACT
Although various syntheses of the nucleic acid bases exist and ribose is a product of the formose reaction, no prebiotically plausible methods for attaching pyrimidine bases to ribose to give nucleosides have been described. Kinetic and thermodynamic factors are thought to mitigate against such condensation reactions in aqueous solution. This inability to produce pyrimidine nucleosides and hence nucleotides is a major stumbling block of the "RNA World" hypothesis and has led to suggestions of alternative nucleic acids as evolutionary precursors to RNA. Here, we show that a process in which the base is assembled in stages on a sugar phosphate can produce cytidine nucleotides. The sequential action of cyanamide and cyanoacetylene on arabinose-3-phosphate produces cytidine-2',3'-cyclophosphate and arabinocytidine-3'-phosphate.
Subject(s)
Cytidine/chemistry , Ribonucleotides/chemistry , Ribonucleotides/chemical synthesis , Sugar Phosphates/chemistry , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
Several alpha-substituted N-carbethoxytropinones have been evaluated as catalysts for asymmetric epoxidation of alkenes with Oxone, via a dioxirane intermediate. alpha-Fluoro-N-carbethoxytropinone (2) has been studied in detail and is an efficient catalyst which does not suffer from Baeyer-Villiger decomposition and can be used in relatively low loadings. This ketone was prepared in enantiomerically pure form using chiral base desymmetrization of N-carbethoxytropinone. Asymmetric epoxidation catalyzed by 2 affords epoxides with up to 83% ee. Among other derivatives tested, the alpha-acetoxy derivative 7 affords the highest enantioselectivities.
