- Identification of Pyrrolo[2,3-d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia
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A series of pyrrolo[2,3-d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G0/G1 stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability (F = 59.5%) and suitable eliminated half-life time (T1/2 = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.
- Yuan, Xue,Chen, Yong,Zhang, Wanhua,He, Jun,Lei, Lei,Tang, Minghai,Liu, Jiang,Li, Muzhou,Dou, Caixia,Yang, Tao,Yang, Linyu,Yang, Shengyong,Wei, Yuquan,Peng, Aihua,Niu, Ting,Xiang, Mingli,Ye, Haoyu,Chen, Lijuan
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Read Online
- HCK AS A THERAPEUTIC TARGET IN MYD88 MUTATED DISEASES
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The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be kinase (e.g., HCK, BTK, LYN, BLK, FRK) inhibitors. Also provided are pharmaceutical compositions and kits including the provided compounds. Further provided are methods of using the provided compounds, pharmaceutical compositions, and kits (e.g., for treating diseases (e.g., proliferative diseases) in a subject in need thereof).
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Paragraph 00291-00292
(2021/04/17)
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- Method for synthesizing 4 -chloropyrropyrimidine compound (by machine translation)
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The invention relates to a synthesis method of 4 -lopyrrolopyrimidine compound, which comprises the following steps: mixing 4 -hydroxypyrrolopyrimidine, phosphorus oxychloride and organic base in a temperature range &at;timetimewise and removing excess ethanol to obtain 3 - 7-amino-4 -iodopyrrolopyrimidine; thirdly, dissolving the product 4 -amino-4 -methyl pyrrolopyrimidine in DMF at room temperature and then drying and concentrating 4 -aminopyrrolopyridine. 4 -aminopyrimidine is dissolved in dichloromethane and then subjected to a heat preservation reaction to get -5 -aminopyrrolopyrimidine; and the mixture is dried to remove the solid insoluble matter and is dried and concentrated to yield 12 hours-aminopyrroyrimidine after the heat preservation reaction is carried out; and the solvent is evaporated to remove the solid insoluble matter and is dried and concentrated to remove the solid insoluble matter 4 -5 -7. (by machine translation)
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- 4-aminopyrrolopyrimidine derivative and preparation method and application thereof
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The invention relates to a 4-aminopyrrolopyrimidine derivative and a preparation method and application thereof, and belongs to the field of medicines. The invention provides a compound shown as a formula I or pharmaceutically acceptable salt thereof. The
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Paragraph 0137-0139; 0147-0148
(2020/05/14)
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- 4-amino-pyrimido azacyclo-phenylurea derivatives, and preparation method and application thereof
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The invention belongs to the field of chemical medicines, and particularly relates to 4-amino-pyrimido azacyclo-phenylurea derivatives, and a preparation method and application thereof. The structuralformula of the 4-amino-pyrimido azacyclo-phenylurea derivatives is represented by formula I in the specification. In addition, the invention further provides the preparation method and the application of the 4-amino-pyrimido azacyclo-phenylurea derivativess. The 4-amino-pyrimido azacyclo-phenylurea derivative provided by the invention can be used as an FLT3 kinase inhibitor, have a good effect, and provide a new choice for preparing antitumor drugs.
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Paragraph 0148-0150; 0153-0154
(2020/09/20)
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- Alkynyl (hetero) aromatic ring compound for inhibiting activity of protein tyrosine kinase
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The present invention relates to an alkynyl (hetero) aromatic ring compound having protein tyrosine kinase inhibition effect, and a preparation method thereof, a pharmaceutical composition containingthe alkynyl (hetero) aromatic ring compound, and uses of
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Paragraph 0292; 0295; 0296; 0297
(2019/09/10)
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- Identification of 5-(2,3-Dihydro-1 H-indol-5-yl)-7 H-pyrrolo[2,3- d]pyrimidin-4-amine Derivatives as a New Class of Receptor-Interacting Protein Kinase 1 (RIPK1) Inhibitors, Which Showed Potent Activity in a Tumor Metastasis Model
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We herein report the structural optimization and structure-activity relationship studies of 5-(2,3-dihydro-1H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine derivatives as a new class of receptor-interacting protein kinase 1 (RIPK1) inhibitors. Among all obtained RIPK1 inhibitors, 1-(5-{4-amino-7-ethyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2,3-dihydro-1H-indol-1-yl)-2-[3-(trifluoromethoxy)phenyl]ethan-1-one (22b) is the most active one. This compound potently inhibited RIPK1 with a binding affinity (KD) of 0.004 μM and an enzymatic IC50 value of 0.011 μM and also showed good kinase selectivity. It could efficiently protect cells from necroptosis and attenuate the necrotic cell death of vascular endothelial cells induced by tumor cells both in vitro and in vivo. Importantly, compound 22b exhibited excellent antimetastasis activity in the experimental B16 melanoma lung metastasis model. It also displayed favorable pharmacokinetic properties. Collectively, 22b could be a promising agent for preventing tumor metastasis.
- Li, Yueshan,Xiong, Yu,Zhang, Guo,Zhang, Liting,Yang, Wei,Yang, Jiao,Huang, Luyi,Qiao, Zeen,Miao, Zhuang,Lin, Guifeng,Sun, Qiu,Niu, Ting,Chen, Lijuan,Niu, Dawen,Li, Linli,Yang, Shengyong
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p. 11398 - 11414
(2019/01/08)
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- THERAPEUTIC INHIBITORY COMPOUNDS
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Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting plasma kallikrein. Furthermore, the subject compounds and compositions are useful for the treatment of diseases wherein the inhibition of plasma kallikrein inhibition has been implicated, such as angioedema and the like.
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Paragraph 00303
(2018/03/26)
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- Synthesis and photophysical evaluation of new fluorescent 7-arylethynyl-7-deazaadenosine analogs
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Three new fluorescent 7-deaza-2′-deoxyadenosine analogs were synthesized via the Sonogashira cross-coupling reaction of 7-iodo-7-deaza-2′-deoxyadenosine with 1-ethynylpyrene, 2-ethynyl-6-methoxynaphthalene, and 9-ethynylphenanthrene. The spectral properties of these analogs were evaluated in dioxane, EtOH, and H2O to determine their potential for use as environmentally sensitive fluorescent probes. All three analogs displayed large solvatofluorochromicity in H2O, relative to their emission wavelengths in dioxane or EtOH. Moreover, all three analogs exhibited microenvironmental sensitivity of their fluorescence emission intensity, being moderate to high quantum yields in dioxane and EtOH and significantly lower in H2O. Various attempts to perform domino cross-coupling and annuation reactions on 7-deaza-7-alkynyladenine derivatives to form a new fused tricyclic adenine analog were unsuccessful.
- Matarazzo, Augusto,Brow, Justin,Hudson, Robert H.E.
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supporting information
p. 1093 - 1100
(2018/11/25)
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- 7H - pyrrolo [2, 3 - d] pyrimidine derivatives (by machine translation)
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The invention of the formula (I) indicated by the 7H - pyrrolo [2, 3 - d] pyrimidine derivatives. The invention provides compound on the tumor cell has prominent inhibit function, can be used for the prevention and/or treatment of tumor-related disorders, particularly lung, and has a wide application. (by machine translation)
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Paragraph 0043-0046
(2017/08/29)
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- COMPOSITIONS AND METHODS FOR TREATING PARASITIC DISEASES
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Disclosed herein, inter alia, are compositions and methods for treating parasitic diseases.
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Paragraph 0813; 0820
(2017/10/11)
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- Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii
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Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.
- Rutaganira, Florentine U.,Barks, Jennifer,Dhason, Mary Savari,Wang, Qiuling,Lopez, Michael S.,Long, Shaojun,Radke, Joshua B.,Jones, Nathaniel G.,Maddirala, Amarendar R.,Janetka, James W.,El Bakkouri, Majida,Hui, Raymond,Shokat, Kevan M.,Sibley, L. David
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supporting information
p. 9976 - 9989
(2018/01/11)
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- PYRROLO[2,3-D]PYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS KINASE INHIBITORS
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The present invention relates to 6-amino-7-deaza-purine derivatives which modulate the activity of protein kinases and are therefore useful in treating diseases caused by dysregulated protein kinase activity, in particular RET family kinases. The present
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Page/Page column 33; 34
(2014/12/12)
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- Synthesis and photophysical characterisation of new fluorescent triazole adenine analogues
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Fluorescent nucleic acid base analogues are powerful probes of DNA structure. Here we describe the synthesis and photo-physical characterisation of a series of 2-(4-amino-5-(1H-1,2,3-triazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7- yl) and 2-(4-amino-3-(1H-1,2,3-triazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl) analogues via Sonogashira cross-coupling and [3 + 2]-cycloaddition reactions as the key steps in the synthesis. Compounds with a nitrogen atom in position 8 showed an approximately ten-fold increase in quantum yield and decreased Stokes shift compared to analogues with a carbon atom in position 8. Furthermore, the analogues containing nitrogen in the 8-position showed a more red-shifted and structured absorption as opposed to those which have a carbon incorporated in the same position. Compared to the previously characterised C8-triazole modified adenine, the emissive potential was significantly lower (tenfold or more) for this new family of triazoles-adenine compounds. However, three of the compounds have photophysical properties which will make them interesting to monitor inside DNA.
- Lawson, Christopher P.,Dierckx, Anke,Miannay, Francois-Alexandre,Wellner, Eric,Wilhelmsson, L. Marcus,Grotli, Morten
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p. 5158 - 5167
(2014/07/08)
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