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
High throughput screening followed by a lead generation campaign uncovered a novel series of urea containing morpholinopyrimidine compounds which act as potent and selective dual inhibitors of mTORC1 and mTORC2. We describe the continued compound optimization campaign for this series, in particular focused on identifying compounds with improved cellular potency, improved aqueous solubility, and good stability in human hepatocyte incubations. Knowledge from empirical SAR investigations was combined with an understanding of the molecular interactions in the crystal lattice to improve both cellular potency and solubility, and the composite parameters of LLE and pIC50-pSolubility were used to assess compound quality and progress. Predictive models were employed to efficiently mine the attractive chemical space identified resulting in the discovery of 42 (AZD3147), an extremely potent and selective dual inhibitor of mTORC1 and mTORC2 with physicochemical and pharmacokinetic properties suitable for development as a potential clinical candidate.
Subject(s)
Drug Discovery , Hepatocytes/drug effects , Multiprotein Complexes/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Thiourea/analogs & derivatives , Cells, Cultured , Hepatocytes/cytology , Humans , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thiourea/chemistry , Thiourea/pharmacologyABSTRACT
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
A rhodium(I) catalyst incorporating the Me-DuPhos ligand promotes enantioselective intermolecular hydroacylation between beta-S-aldehydes and 1,3-disubstituted allenes. The nonconjugated enone products are obtained in good yields and with high enantioselectivities.
Subject(s)
Aldehydes/chemistry , Alkenes/chemistry , Chemistry/methods , Rhodium/chemistry , Carbon/chemistry , Catalysis , Ligands , Metals/chemistry , Models, Chemical , Molecular Structure , Stereoisomerism , TemperatureABSTRACT
The use of beta-S-substituted aldehydes in rhodium-catalyzed intermolecular hydroacylation reactions is reported. Aldehydes substituted with either sulfide or thioacetal groups undergo efficient hydroacylation with a variety of electron-poor alkenes, such as enoates, in Stetter-like processes and with both electron-poor and neutral alkynes. In general, the reactions with electron-poor alkenes demonstrate good selectivity for the linear regioisomer, and the reactions with alkynes provide enone products with excellent selectivity for the E-isomers. The scope of the process was shown to be broad, tolerating a variety of substitution patterns and functional groups on both reaction components. A novel CN-directing effect was shown to be responsible for reversing the regioselectivity in a number of alkyne hydroacylation reactions. Catalyst loadings as low as 0.1 mol % were achievable.
Subject(s)
Aldehydes/chemistry , Alkenes/chemistry , Alkynes/chemistry , Ketones/chemical synthesis , Rhodium/chemistry , Catalysis , Ketones/chemistry , Molecular Structure , StereoisomerismABSTRACT
[reaction: see text]. Beta-thioacetal-substituted aldehydes, which are conveniently prepared from the corresponding ynals, can be combined with a range of alkynes or electron-poor alkenes to deliver intermolecular hydroacylation adducts. The reactions employ [Rh(dppe)]ClO4 as a catalyst and are proposed to proceed via a chelated rhodium acyl intermediate. The thioacetal-containing products can be deprotected to the corresponding ketones or reduced to alkanes in good yields.
ABSTRACT
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.