72784-47-5Relevant articles and documents
Structure-Based Design of Potent and Orally Active Isoindolinone Inhibitors of MDM2-p53 Protein-Protein Interaction
Chessari, Gianni,Hardcastle, Ian R.,Ahn, Jong Sook,Anil, Burcu,Anscombe, Elizabeth,Bawn, Ruth H.,Bevan, Luke D.,Blackburn, Timothy J.,Buck, Ildiko,Cano, Celine,Carbain, Benoit,Castro, Juan,Cons, Ben,Cully, Sarah J.,Endicott, Jane A.,Fazal, Lynsey,Golding, Bernard T.,Griffin, Roger J.,Haggerty, Karen,Harnor, Suzannah J.,Hearn, Keisha,Hobson, Stephen,Holvey, Rhian S.,Howard, Steven,Jennings, Claire E.,Johnson, Christopher N.,Lunec, John,Miller, Duncan C.,Newell, David R.,Noble, Martin E. M.,Reeks, Judith,Revill, Charlotte H.,Riedinger, Christiane,St. Denis, Jeffrey D.,Tamanini, Emiliano,Thomas, Huw,Thompson, Neil T.,Vinkovi?, Mladen,Wedge, Stephen R.,Williams, Pamela A.,Wilsher, Nicola E.,Zhang, Bian,Zhao, Yan
supporting information, p. 4071 - 4088 (2021/05/04)
Inhibition of murine double minute 2 (MDM2)-p53 protein-protein interaction with small molecules has been shown to reactivate p53 and inhibit tumor growth. Here, we describe rational, structure-guided, design of novel isoindolinone-based MDM2 inhibitors. MDM2 X-ray crystallography, quantum mechanics ligand-based design, and metabolite identification all contributed toward the discovery of potent in vitro and in vivo inhibitors of the MDM2-p53 interaction with representative compounds inducing cytostasis in an SJSA-1 osteosarcoma xenograft model following once-daily oral administration.
Group-Based Optimization of Potent and Cell-Active Inhibitors of the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Structure-Activity Relationships Leading to the Chemical Probe (2S,4R)-1-((S)-2-(1-Cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)
Soares, Pedro,Gadd, Morgan S.,Frost, Julianty,Galdeano, Carles,Ellis, Lucy,Epemolu, Ola,Rocha, Sonia,Read, Kevin D.,Ciulli, Alessio
, p. 599 - 618 (2018/02/07)
The von Hippel-Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants 100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways and new VHL ligands for next-generation PROTACs.
PROCESS FOR THE PREPARATION OF CYCLOPROPYLDIKETOPIPERAZINES AND OF A KEY INTERMEDIATE OF DS-5272
-
Paragraph 00138; 00140, (2018/09/08)
Object of the present invention is an improved process for the preparation of cyclopropyldiketopiperazines and thereof key intermediates.
A 1-amino-cyclopropane-1-carboxylic acid simple synthesis process
-
Paragraph 0019; 0020, (2017/02/24)
The invention relates to a synthesis process of 1-aminocyclopropane-1-carboxylic acid. According to the process, the 1-aminocyclopropane-1-carboxylic acid is synthesized from nitro acetate and 1,2-dihalo ethane through the reaction of alkylated cyclization, nitro reduction and carboxyl hydrolysis, and a high-content and high-purity product is obtained through carrying out separation, purification and crystallization after the reaction is ended. In the aspects of reagents and raw and auxiliary materials used during the reaction, both environment-friendliness and efficiency are taken into account. The process disclosed by the invention has the advantages of high atom economical efficiency, simple equipment and environment-friendly production procedure and has very large economic and social benefits.
NOVEL COMPOUNDS
-
Page/Page column 117, (2014/10/03)
The present invention relates substituted N-biphenyl-3-acetylamino-benzamides and N-[3-(acetylamino)phenyl]-biphenyl-carboxamides of general formula (I) as described and defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper-proliferative disorder, as a sole agent or in combination with other active ingredients.
Chemokine receptor binding heterocyclic compounds with enhanced efficacy
-
Page/Page column 49-50, (2010/02/03)
The invention relates to heterocyclic compounds consisting of a core nitrogen atom surrounded by three pendant groups, wherein two of the three pendant groups are preferably benzimidazolyl methyl and tetrahydroquinolyl, and the third pendant group contains N and optionally contains additional rings. The compounds bind to chemokine receptors, including CXCR4 and CCR5, and demonstrate protective effects against infection of target cells by a human immunodeficiency virus (HIV).
Partial agonists of the strychnine insensitive glycine modulatory site of the N-methyl-D-aspartate receptor complex as neuropsychopharmacological agents
-
, (2008/06/13)
A method is disclosed for the treatment of neuropsychopharmacological disorders which are associated with or result from excessive activation of the N-methyl-D-aspartate receptor complex, which method comprises administering an effective neuropsychopharmacological disorder-treating amount of a compound possessing partial agonist properties for the strychnine insensitive glycine modulatory sites of N-methyl-D-aspartate receptors. Exemplary of partial agonists which are useful in the method of the invention are 1-aminocyclopropanecarboxylic acid, and associated derivates thereof. Novel injectable pharmaceutical compositions are also disclosed.
BENZAMIDINE DERIVATIVES SUBSTITUTED BY CYCLIC AMINO ACID AND CYCLIC HYDROXY ACID DERIVATIVES AND THEIR USE AS ANTI-COAGULANTS
-
, (2008/06/13)
This invention is directed to benzamidine derivatives substituted by cyclic amino acid and cyclic hydroxy acid derivatives which are useful as anti-coagulants. This invention is also directed to pharmaceutical compositions containing the compounds of the invention, and methods of using the compounds to treat disease-states characterized by thrombotic activity.
Treatment of mood disorders with functional antagonists of the glycine/NMDA receptor complex
-
, (2008/06/13)
A method is disclosed for the treatment of mood disorders, including major depression, by administering an effective mood disorder treating amount of a compound possessing functional antagonist properties for the N-methyl-D-aspartate receptor complex.
Latent Inhibitors. Part 5. Latent Inhibition of Dihydrofolate Reductase by a Pteridine-spiro-cyclopropane
Haddow, John,Suckling, Colin J.,Wood, Hamish C. S.
, p. 1297 - 1304 (2007/10/02)
The design of cyclopropane-containing enzyme activated inhibitors of dihydrofolate reductase is presented.The synthesis of two examples, 2-amino-7,8-dihydro-6-hydroxymethylpteridine-7-spirocyclopropan-4(3H)-one and 2,4-diamino-5-(4-chlorophenyl)-6-cyclopropylpyrimidine, is described.Kinetic studies with dihydrofolate reductase from E. coli are presented to show that the former is a time-dependent inhibitor of the enzyme whereas the latter is a typical competitive inhibitor.The results are interpreted with regard to the active site structure of dihydrofolate reductase.
