- Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors
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Minor structural modifications - sometimes single atom changes - can have a dramatic impact on the properties of compounds. This is illustrated here on structures related to known mTOR inhibitor Sapanisertib. Subtle changes in the hinge binder lead to strikingly different overall profiles with changes in physical properties, metabolism, and kinase selectivity.
- Ouvry, Gilles,Clary, Laurence,Tomas, Lo?c,Aurelly, Michèle,Bonnary, Laetitia,Borde, Emilie,Bouix-Peter, Claire,Chantalat, Laurent,Defoin-Platel, Claire,Deret, Sophie,Forissier, Mathieu,Harris, Craig S.,Isabet, Tatiana,Lamy, Laurent,Luzy, Anne-Pascale,Pascau, Jonathan,Soulet, Catherine,Taddei, Alessandro,Taquet, Nathalie,Thoreau, Etienne,Varvier, Emeric,Vial, Emmanuel,Hennequin, Laurent F.
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Read Online
- ADENOSINE RECEPTOR ANTAGONIST COMPOUNDS
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The present disclosure provides adenosine receptor (e.g., A2A and/or A1 receptor) antagonist compounds and compositions including said compounds. The present disclosure also provides methods of using said compounds and compositions for modulating (e.g., inhibiting or antagonizing) A2A and/or A1 receptor in a biological system. The compounds and compositions find use in various therapeutic applications including the treatment of cancer and in immuno-oncology. The compounds and compositions find use in various therapeutic applications including the treatment of central nervous system or neurodegenerative diseases, such as Parkinson's disease.
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Paragraph 00339-00342
(2021/05/29)
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- ADENOSINE A2A RECEPTOR ANTAGONISTS AND USES THEREOF
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Disclosed herein are compounds, compositions, and methods for modulating the A2A2A adenosine receptor with the compounds and compositions disclosed herein. Also described are methods of treating diseases or disorders that are mediated by the A
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Paragraph 00280-00281
(2021/02/12)
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- Fused pyrimidine derivatives substituted with a nitrogen-containing heterocyclic ring and their pharmaceutical use
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The present application relates to fused pyrimidine derivatives substituted with heterocycles containing nitrogen and to their medicinal use. Provided are a compound represented by chemical formula I, a solvate, a stereoisomer thereof, a pharmaceutically
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Paragraph 0191-0196
(2021/07/17)
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- Development of18f-labeled radiotracers for pet imaging of the adenosine a2a receptor: Synthesis, radiolabeling and preliminary biological evaluation
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The adenosine A2A receptor (A2AR) represents a potential therapeutic target for neuro-degenerative diseases. Aiming at the development of a positron emission tomography (PET) radio-tracer to monitor changes of receptor density and/or occupancy during the
- Lai, Thu Hang,Schr?der, Susann,Toussaint, Magali,Duki?-Stefanovi?, Sladjana,Kranz, Mathias,Ludwig, Friedrich-Alexander,Fischer, Steffen,Steinbach, J?rg,Deuther-Conrad, Winnie,Brust, Peter,Moldovan, Rare?-Petru
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- Development of pyrazolo[3,4-d]pyrimidine-6-amine-based TRAP1 inhibitors that demonstrate in vivo anticancer activity in mouse xenograft models
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TNF Receptor Associated Protein 1 (TRAP1) is a mitochondrial paralog of Hsp90 related to the promotion of tumorigenesis in various cancers via maintaining mitochondrial integrity, reducing the production of reactive oxygen species, and reprogramming cellular metabolism. Consequently, Hsp90 and TRAP1 have been targeted to develop cancer therapeutics. Herein, we report a series of pyrazolo[3,4-d]pyrimidine derivatives that are mitochondria-permeable TRAP1 inhibitors. Structure-based drug design guided the optimization of potency, leading to the identification of compounds 47 and 48 as potent TRAP1 and Hsp90 inhibitors with good metabolic and plasma stability as well as acceptable CYP and hERG inhibition. X-ray co-crystallization studies confirmed both 47 and 48 interact with the ATP binding pocket in the TRAP1 protein. Compounds 47 and 48 demonstrated excellent anticancer efficiency in various cancer cells, with limited toxicity over normal hepatocyte and prostate cells. Mouse PC3 xenograft studies showed 47 and 48 significantly reduced tumor growth.
- Hong, Ki Bum,Kang, Byoung Heon,Kang, Soosung,Kim, Darong,Kim, Dongyoung,Kim, So-Yeon,Lee, Changwook,Lee, Ji Hoon,Yoon, Nam Gu,Yun, Jisu
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- Application of five-membered heterocycle pyrimidine compound
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The invention belongs to the field of medicine and particularly relates to application of a five-membered heterocycle pyrimidine compound with the structural features as shown in formula (I) and the pharmaceutically acceptable salt of the five-membered heterocycle pyrimidine compound serving as nucleotide oxidative damage repairase MTH1 inhibitors. Pharmacological experiment results show that thecompound can evidently inhibit the activity of MTH1 and can be used for preventing and treating clinical diseases related to MTH1.
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Paragraph 0113; 0114; 0117; 0118
(2018/09/12)
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- nitrogen hybridization guanine nucleoside and its synthetic method and the use of DNA sequencing
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The invention discloses hybrid azaguanosine as well as a synthesis method and an application thereof in DNA sequencing. The synthesis method comprises the steps: removing a protecting group of a compound as shown in formula (III) in the specification under an alkaline condition to obtain a compound as shown in formula (II) in the specification; further demethylating to obtain a compound as shown in formula (I) in the specification, i.e. 7-deaza-7-halogen-8-aza-guanosine, wherein R1 is H or OH, R2 is I, Br or Cl, and R3 is H or a compound shown in the specification. The hybrid azaguanosine disclosed by the invention is a novel reagent for DNA sequencing, which, compared to guanosine failing to substitute nitrogen on 8 sites, is more excellent in base identifying effect and more stable in DNA chain structure. Meanwhile, different from the prior art that 8-site nitrogen-substituted guanosine is complex in synthesis method, low in yield and unsuitable for commercial production, the synthesis method disclosed by the invention is easily available in raw material required, and adopts conventional chemical synthesis reaction; and the method is relatively high in yield, and suitable for wide popularization and application.
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Paragraph 0076; 0082; 0083; 0084
(2016/10/27)
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- THERAPEUTICALLY ACTIVE PYRAZOLO-PYRIMIDINE DERIVATIVES
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A series of pyrazolo[3,4-d]pyrimidine derivatives that are substituted at the 4- position by a diaza monocyclic, bridged bicyclic or spirocyclic moiety, are beneficial in the treatment and/or prevention of various human ailments, including inflammatory, autoimmune and oncological disorders; viral diseasesand malaria; and organ and cell transplant rejection.
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Page/Page column 50
(2014/07/08)
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- METABOLITES OF 2-(FURAN-2-YL)-7-(2-(4-(4-(2-METHOXYETHOXY)PHENYL)PIPERAZIN-1-YL)ETHYL)-7H-PYRAZOLO[4,3-e][1,2,4]TRIAZOLO[1,5-c]PYRIMIDIN-5-AMINE AND THEIR UTILITY AS ADENOSINE A2a RECEPTOR ANTAGONISTS
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The present invention provides a compound of the (formula:(I) or a pharmaceutically acceptable salt thereof in isolated and purified form. The compound is an adenosine A2a receptor antagonists useful in treatment of central nervous system disorders, such
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Page/Page column 17
(2012/10/18)
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- HETEROCYCLIC COMPOUNDS AND METHODS OF USE
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Formula I compounds, including stereoisomers, geometric isomers, tautomers, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting the delta isoform of PI3K, and for treating disorders mediated by lipid kinases such as inflammation, immunological disorders, and cancer. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.
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Page/Page column 262
(2012/08/27)
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- METABOLITES OF 7-(2-(4-(6-FLUORO-3-METHYLBENZO[d]ISOXAZOL-5-YL)PIPERAZIN-1-YL)ETHYL)-2-(PROP-1-YNYL)-7H-PYRAZOLO [4,3-e][1,2,4]TRIAZOLO[1,5-c]PYRIMIDIN-5-AMINE AND THEIR UTILITY AS ADENOSINE A2a RECEPTOR ANTAGONISTS
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The present invention provides a compound of the Formula I: Formula I or a pharmaceutically acceptable salt thereof in isolated and purified form wherein R, R1 and R2 are as described herein. The compounds are adenosine A2a receptor antagonists useful in treatment of central nervous system disorders, such as Parkinsons disease, Extra-Pyramidal Syndrome (EPS) caused by treatment with an antipsychotic agent, restless legs syndrome, Huntington s disease, attention disorders, depression, stroke and psychoses
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Page/Page column 20
(2012/10/18)
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- Synthesis of novel 2-cyano-7-deaza-8-azapurine- and 2-cyano-8-azapurine- derived nucleosides
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A novel systematic approach to the synthesis of 2-cyano-7-deaza-8-azapurine derived nucleosides is described. It is shown how this chemistry was developed with the labile 2-substituted nitrile position in mind, and also how the same approach is applicable to 2-cyano-8-azapurine derived nucleosides.
- Wainwright, Philip,Maddaford, Adrian,Simms, Michael,Forrest, Neil,Glen, Rebecca,Hart, James,Zhang, Xiurong,Pryde, David C.,Stephenson, Peter T.,Middleton, Donald S.,Guyot, Thierry,Sutton, Scott C.
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scheme or table
p. 1900 - 1904
(2011/10/08)
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- Potent and selective adenosine A2A receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones
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Antagonism of the adenosine A2A receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidi
- Harris, Joel M.,Neustadt, Bernard R.,Zhang, Hongtao,Lachowicz, Jean,Cohen-Williams, Mary,Varty, Geoff,Hao, Jinsong,Stamford, Andrew W.
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scheme or table
p. 2497 - 2501
(2011/05/15)
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- HETEROCYCLIC GTP CYCLOHYDROLASE 1 INHIBITORS FOR THE TREATMENT OF PAIN
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The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).
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Page/Page column 77
(2011/04/19)
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- PYRAZOLO [3, 4-D] PYRIMIDINE DERIVATIVES USEFUL TO TREAT RESPIRATORY DISORDERS
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The present invention concerns a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, where R1-R3 and Y are defined in the description, and its use in the treatment of disorders in which pi3 kinase is imp
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Page/Page column 70
(2008/06/13)
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- 2-Heteroaryl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1-isoxazolyl, R1-oxadiazolyl, R1-dihydrofuranyl, R1-pyrazolyl, R1-imidazolyl, R1-pyrazinyl or R1-pyrimidinyl; R1 is 1, 2 or 3 substituents selected from H, alkyl, alkoxy and halo; Z is optionally substituted-aryl, or optionally substituted-heteroaryl; are disclosed, as well as their use in the treatment of central nervous system diseases, in particular Parkinson's disease and Extra Pyramidal Syndrome, pharmaceutical compositions comprising them, and combinations with other agents.
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Page/Page column 6; 8
(2008/06/13)
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- Pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted phenyl, furanyl, thienyl, pyridyl, pyridyl N-oxide, oxazolyl or pyrrolyl, or cycloalkenyl R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; and Z is optionally substituted aryl or heteroaryl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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Page/Page column 10
(2008/06/13)
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- 2-Alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine A2a receptor antagonists
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Compounds having the structural formula I or a pharmaceutically acceptable salt thereof, wherein R is R1, R2, R3, R4 and R5 are H, alkyl or alkoxyalkyl; R6 is H, alkyl, hydroxyalkyl or —CH2F; R7, R8 and R9 are H, alkyl, alkoxy, alkylthio, alkoxyalkyl, halo or —CF3; and Z is optionally substituted aryl, heteroaryl or heteroaryl-alkyl are disclosed. Also disclosed is the use of compounds of formula I in the treatment of central nervous system diseases, in particular Parkinson's disease, alone or in combination with other agents for treating Parkinson's disease, and pharmaceutical compositions comprising them.
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- Process for the synthesis of pyrazolopyrimidines
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The present invention provides a nucleoside comprising a pyrazolopyrimidine base and a process for producing the same. In particular, the processes of the present invention comprises using a halogenated pyrazolopyrimidine base and removing the halogen after the base is coupled to a sugar moiety. The presence of the halogen on the nucleoside base allows facile and economical production of a large quantity of nucleosides.
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- SYNTHESIS OF THE β-D-DEOXYRIBOFURANOSIDE OF 6-AMINO-1H-PYRAZOLO-PYRIMIDIN -4(5H)-ONE - A NEW ISOSTER OF 2'-DEOXYGUANOSINE
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6-Amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1H-pyrazolopyrimidin-4(5H)-one (8) has been synthesized via regio- and diastereo-selective phase-transfer glycosylation of 6-amino-4-methoxy-1H-pyrazolopyrimidine (4) with 2-deoxy-3,5-di-O-(p-to
- Seela, Frank,Steker, Herbert
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p. 2521 - 2524
(2007/10/02)
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