ABSTRACT
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
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 collection of novel, pharmaceutically relevant cubane-containing molecules has been prepared from the commercially available cubane-1,4-dimethylester. A range of synthetic methods have been applied to prepare these cubane building blocks with one or two functional handles to allow easy incorporation into existing medicinal chemistry programs.
Subject(s)
Bridged-Ring Compounds/chemistry , Chemistry, Pharmaceutical , Heterocyclic Compounds/chemistry , Models, Molecular , Molecular StructureABSTRACT
Ghrelin plays a major physiological role in the control of food intake, and inverse agonists of the ghrelin receptor (GHS-R1a) are widely considered to offer utility as antiobesity agents by lowering the set-point for hunger between meals. We identified an acylurea series of ghrelin modulators from high throughput screening and optimized binding affinity through structure-activity relationship studies. Furthermore, we identified specific substructural changes, which switched partial agonist activity to inverse agonist activity, and optimized physicochemical and DMPK properties to afford the non-CNS penetrant inverse agonist 22 (AZ-GHS-22) and the CNS penetrant inverse agonist 38 (AZ-GHS-38). Free feeding efficacy experiments showed that CNS exposure was necessary to obtain reduced food intake in mice, and it was demonstrated using GHS-R1a null and wild-type mice that this effect operates through a mechanism involving GHS-R1a.
Subject(s)
Drug Inverse Agonism , Receptors, Ghrelin/agonists , Receptors, Ghrelin/antagonists & inhibitors , Urea/analogs & derivatives , Urea/pharmacology , Dose-Response Relationship, Drug , Humans , Models, Molecular , Molecular Structure , Receptors, Ghrelin/metabolism , Structure-Activity Relationship , Urea/chemistryABSTRACT
The synthesis of silaheterocycles through the first examples of an intramolecular silene Diels-Alder reaction is described.
ABSTRACT
A new series of pyrazinecarboxamide DGAT1 inhibitors was designed to address the need for a candidate drug with good potency, selectivity, and physical and DMPK properties combined with a low predicted dose in man. Rational design and optimization of this series led to the discovery of compound 30 (AZD7687), which met the project objectives for potency, selectivity, in particular over ACAT1, solubility, and preclinical PK profiles. This compound showed the anticipated excellent pharmacokinetic properties in human volunteers.
Subject(s)
Acetates/chemistry , Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Pyrazines/chemistry , Acetates/pharmacokinetics , Acetates/pharmacology , Animals , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Magnetic Resonance Spectroscopy , Pyrazines/pharmacokinetics , Pyrazines/pharmacology , Rats , SolubilityABSTRACT
A formal synthesis of merrilactone A has been completed using a domino 1,4-addition-aldol process as the key step. Both iodo- and cyano-1,4-addition-aldol cyclizations were productive in forming the highly hindered C1-C9 bond linking vic-quaternary and tertiary stereocenters. The latter method was used to complete a formal total synthesis of the natural product.
Subject(s)
Cyanides/chemistry , Lactones/chemical synthesis , Sesquiterpenes/chemical synthesis , Cyclization , Lactones/chemistry , Molecular Structure , Sesquiterpenes/chemistry , StereoisomerismABSTRACT
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Oxadiazoles/chemical synthesis , Animals , Diabetes Mellitus/drug therapy , Diacylglycerol O-Acyltransferase/metabolism , Dogs , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Half-Life , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Ligands , Mice , Obesity/drug therapy , Oxadiazoles/pharmacokinetics , Quantitative Structure-Activity Relationship , RatsABSTRACT
[structure: see text] A highly stereocontrolled total synthesis of the cytotoxic macrolide (-)-callipeltoside A has been achieved in 23 steps (4.8% overall). Notable features include a novel asymmetric vinylogous aldol reaction to install the C13 stereocenter and (E)-trisubstituted alkene, an anti-selective aldol addition, a Sonogashira coupling, and, last, a Schmidt-type glycosylation to attach the sugar unit.
Subject(s)
Macrolides/chemical synthesis , StereoisomerismABSTRACT
Following macrolactonization, a Sonogashira coupling leads efficiently from 1 and 2 to the aglycon of the structurally unique cytotoxic macrolide callipeltoside A, isolated in tiny quantities from the lithistid sponge Callipelta sp. Key steps in the preparation of macrolide precursor 1 include a boron-mediated anti-aldol coupling (A) in tandem with Yamamoto's vinylogous aldol reaction (B). TES=triethylsilyl.
