- A novel pyrazolo [3,4-d] pyrimidine, KKC080106, activates the Nrf2 pathway and protects nigral dopaminergic neurons
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The transcription factor nuclear factor-erythroid 2-related factor-2 (Nrf2) is known to induce neuroprotective and anti-inflammatory effects and is considered to be an excellent molecular target for drugs related to neurodegenerative disease therapy. Nrf2 activators previously tested in clinical trials were electrophilic, causing adverse effects due to non-selective and covalent modification of cellular thiols. In order to circumvent this issue, we constructed and screened a chemical library consisting of 241 pyrazolo [3,4-d] pyrimidine derivatives and discovered a novel, non-electrophilic compound: 1-benzyl-6-(methylthio)-N-(1-phenylethyl)-1H-pyrazolo[3,4-d]pyrimidine-4-amine (KKC080106). KKC080106 was able to activate Nrf2 signaling as it increases the cellular levels of Nrf2, binds to the Nrf2 inhibitor protein Keap1, and causes the accumulation of nuclear Nrf2. We also observed an increase in the expression levels of Nrf2-dependent genes for antioxidative/neuroprotective enzymes in dopaminergic neuronal cells. In addition, in lipopolysaccharide-activated microglia, KKC080106 suppressed the generation of the proinflammatory markers, such as IL-1β, TNF-α, cyclooxygenase-2, inducible nitric oxide synthase, and nitric oxide, and inhibited the phosphorylation of kinases known to be involved in inflammatory signaling, such as IκB kinase, p38, JNK, and ERK. As a drug, KKC080106 exhibited excellent stability against plasma enzymes and a good safety profile, evidenced by no mortality after the administration of 2000 mg/kg body weight, and minimal inhibition of the hERG channel activity. Pharmacokinetic analysis revealed that KKC080106 has good bioavailability and enters the brain after oral and intravenous administration, in both rats and mice. In MPTP-treated mice that received KKC080106 orally, the compound blocked microglial activation, protected the nigral dopaminergic neurons from degeneration, and prevented development of the dopamine deficiency-related motor deficits. These results suggest that KKC080106 has therapeutic potential for neurodegenerative disorders such as Parkinson's disease.
- Cheong, Chan Seong,Han, Se Hee,Hwang, Onyou,Kim, Dong Jin,Kim, Hye Ri,Lee, Ji Ae,Shin, Nari,Son, Hyo Jin
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- NEW PYRIMIDINE DERIVATIVES FOR PREVENTION AND TREATMENT OF GRAM-NEGATIVE BACTERIAL INFECTION, CONTAMINATION AND FOULING
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New pyrimidine derivatives together with a membrane penetrating agent, optionally with a detectable isotope and pharmaceutical composition for use in treatment or prevention of Gram-negative bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of Gram-negative biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. New pyrimidine derivatives together with a membrane penetrating agent; for use as radiotracer in diagnosing or prognosing Gram-negative bacterial infection in a host mammal.
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Page/Page column 99
(2020/10/28)
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- PYRIMIDINE DERIVATIVES FOR PREVENTION AND TREATMENT OF BACTERIAL INFECTIONS
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New pyrimidine derivatives of formula (I), optionally with a detectable isotope, pharmaceutical composition and method of preparation thereof. New pyrimidine derivatives for use in treatment or prevention of bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. New pyrimidine derivatives for use as radiotracer in diagnosing or prognosing bacterial infection in a host mammal.
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Page/Page column 87
(2019/09/04)
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- HETEROARYL DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL COMPOSTION FOR PREVENTING OR TREATING DISEASES ASSOCIATED WITH PI3 KINASES, CONTAINING SAME AS ACTIVE INGREDIENT
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The present invention relates to a heteroaryl derivative or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a pharmaceutical composition for preventing or treating diseases associated with PI3 kinases, containing the same as an active ingredient. The heteroaryl derivative according to the present invention has an excellent effect of selectively inhibiting PI3 kinases, thereby being useful in preventing or treating PI3 kinase diseases such as: cancers, autoimmune diseases, and respiratory diseases.
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Paragraph 0797-0799; 0995-0997
(2018/04/26)
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- Exploring the chemical space around the privileged pyrazolo[3,4-d] pyrimidine scaffold: Toward novel allosteric inhibitors of T315I-mutated Abl
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A library of pyrazolo[3,4-d]pyrimidines, endowed with a high level of molecular diversity, has been developed applying a synthetic sequence that allowed C3, N1, C4, and C6 substitution. The enzymatic screening of this "privileged scaffold"-based compound collection, validated the use of a diversity-oriented approach in a field characteristically explored by target-oriented synthesis. In fact, several compounds showed high activity against the selected kinases (i.e., Src, Abl wt, and T315I mutated-form), furthermore and interestingly a new compound has emerged as an allosteric inhibitor of the T315I mutated-form of Abl, opening up new opportunities for the development of a novel class of noncompetitive inhibitors of Abl (T315I).
- Vignaroli, Giulia,Mencarelli, Martina,Sementa, Deborah,Crespan, Emmanuele,Kissova, Miroslava,Maga, Giovanni,Schenone, Silvia,Radi, Marco,Botta, Maurizio
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supporting information
p. 168 - 175
(2014/05/06)
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- FUSED HETEROCYCLIC RING DERIVATIVE AND USE THEREOF
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The present invention provides a fused heterocycle derivative having a strong Smo inhibitory activity, and use thereof. Specially, the present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or salt thereof, and a medicament containing the compound or a prodrug thereof, which is an Smo inhibitor or an agent for the prophylaxis or treatment of cancer.
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Page/Page column 57-58
(2012/07/14)
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- ALICYCLIC HETEROCYCLIC COMPOUND
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An alicyclic heterocyclic compound represented by the following formula or a pharmaceutically acceptable salt thereof: wherein ring A is a heterocyclic ring, ring B is a carbocyclic ring, a heterocyclic ring etc., P1 and P2 are CH or N, q and r are 0 to 2, X is -NH-, -O-, -CH2-, etc., Y is -CH2-, -CO-, -SO2-, etc., Z is -CO-, -SO2-, etc., and R3 is carbocyclic group, heterocyclic group, hydroxyl, alkoxy or amino, is useful as a controlling agent of the function of CCR4 useful for the prevention or treatment for bronchial asthma, atopic dermatitis, etc.
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Page/Page column 35
(2008/12/08)
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- NOVEL COMPOUNDS
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Novel substituted 2,4,8-trisubstituted 8H-pyrido[2,3-d]pyrimidin-7-one containing compounds and compositions, and their use use in therapy as CSBP/RK/p38 kinase inhibitors.
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Page/Page column 107-108
(2008/06/13)
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- FUSED PYRAZOLE AS p38 MAP KINASE INHIBITORS
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Fused pyrazoles effective as p38 MAP kinase inhibitors, methods of making the compounds, and methods of using the compounds for treatment of p38 MAP kinase-mediated diseases.
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Page/Page column 53; 69-70
(2008/06/13)
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- INHIBITORS OF TNFα, PDE4 AND B-RAF, COMPOSITIONS THEREOF AND METHODS OF USE THEREWITH
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Provided herein are compounds having TNFα and/or PDE4 and/or B-RAF inhibitory activity, and compositions thereof. In particular, provided herein are compounds of the formula (I) and pharmaceutically acceptable salts, solvates, hydrates, clathrates, stereoisomers, polymorphs and prodrugs thereof, wherein Ar, R1, R2, R3, R4, n and Z are as described herein. Further provided herein are methods for treating or preventing various diseases and disorders by administering to a patient one or more TNFα and/or PDE4 and/or B-RAF inhibitors. In particular, provided herein are methods for preventing or treating cancer, inflammatory disorders, cognition and memory disorders and autoimmune disorders, or one or more symptoms thereof by administering to a patient one or more TNFα and/or PDE4 and/or B-RAF inhibitors.
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Page/Page column 105-106
(2010/11/28)
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- MODIFIED MALONATE DERIVATIVES
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The present invention relates to a novel class of modified malonate derivatives. The modified malonate compounds can be used to treat cancer. The modified malonate compounds can also inhibit histone deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention may also be useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases. The present invention further provides pharmaceutical compositions comprising the modified malonate derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the modified malonate derivatives in vivo.
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Page/Page column 88
(2010/11/25)
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- NOVEL COMPOUNDS
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Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds, and 1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-(1H)-one compounds and compositions, and their use in therapy as CSBP/RK/p38 kinase inhibitors.
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Page/Page column 78-79
(2008/06/13)
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- NOVEL COMPOUNDS
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Novel substituted 1,5,7-trisubstituted-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2-(1H)-one compounds and compositions, and their use in therapy as CSBP/RK/p38 kinase inhibitors.
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Page/Page column 101-102
(2010/11/29)
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- NOVEL COMPOUNDS
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Novel substituted l,5,7-trisubstituted-354-dihydro-pyriinido[4,5-(flpyrimidin- 2-(2H)-one compounds and compositions, and their use in therapy as CSBP/RK/p38 kinase inhibitors.
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Page/Page column 113-114
(2008/06/13)
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- PROCESS FOR PREPARING PYRIDO[2,3-D]PYRIMIDIN-7-ONE AND 3,4-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-2(1H)-ONE DERIVATIVES
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The present invention is directed to a novel method of preparing of 2,4,8- trisubstituted pyrido[2,3-d]pyrimidin-7-one pharmacophores of Formula (II) or (Ha) wherein GHs CH2 Or NH: G2 is CH or nitrogen; Rx is chloro, bromo, iodo, or O-S(O)
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Page/Page column 81-82
(2008/06/13)
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- NOVEL COMPOUNDS
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Novel substituted 2,4,8-trisubstituted 8H-pyrido[2,3-d]pyrimidin-7-one containing compounds and compositions, and their use use in therapy as CSBP/RK/p38 kinase inhibitors.
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Page/Page column 122
(2008/06/13)
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- Fused-pyrazolo pyrimidine and pyrazolo pyrimidinone derivatives and methods for using the same
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Compounds of the formula Ia or Ib: wherein A, B, X, Y, Z, W, k, R1, R2, R3, R4 and R5 are those defined herein, and compositions comprising the same. The present invention also provides methods for pr
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Page/Page column 73-74
(2010/02/13)
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- Heteroaryl-fused pyrazolo derivatives and methods for using the same
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Compounds of the formula I: where A, B, X, Y, Z, k, R1, R2 and R3 are those defined herein, and compositions comprising the same. The present invention also provides methods for preparing compounds of formula I and using t
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Page/Page column 52-53
(2010/02/13)
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