- Discovery of (E)-N-(4-methyl-5-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-yl)thiazol-2-yl)-2-(4-methylpiperazin-1-yl)acetamide (IHMT-TRK-284) as a novel orally available type II TRK kinase inhibitor capable of overcoming multiple resistant mutants
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Due to the critical tumorigenic role of fused NTRK genes in multiple cancers, TRK kinases have attracted extensive attention as a drug discovery target. Starting from an indazole based scaffold, through the type II kinase inhibitor fragments hybrid design approach with a ring closure strategy, we discovered a novel potent type II TRK kinase inhibitor compound 34 (IHMT-TRK-284), which exhibited IC50 values of 10.5 nM, 0.7 nM and 2.6 nM to TRKA, B, and C respectively. In addition, it displayed great selectivity profile in the kinome when tested among 468 kinases and mutants (S score (1) = 0.02 at 1 μM). Importantly, 34 could overcome drug resistant mutants including V573M and F589L in the ATP binding pocket as well as G667C/S in the DFG region. In vivo, 34 exhibited good PK profiles in different species including mice, rats, and dogs. It also displayed good in vivo antitumor efficacies in the TRKA/B/C, TRKA mutants, and KM-12-LUC cells mediated mouse models. The potent activity against clinically important TRK mutants combined with the good in vivo PK and efficacy properties of 34 indicated that it might be a new potential therapeutic candidate for TRK kinase fusion or mutants driven cancers.
- Chen, Cheng,Chen, Yongfei,Hu, Chen,Hu, Zhenquan,Jiang, Zongru,Liu, Jing,Liu, Qingsong,Liu, Qingwang,Liu, Xuesong,Qi, Shuang,Wang, Aoli,Wang, Beilei,Wang, Junjie,Wang, Li,Wang, Wenchao,Zhang, Wentao,Zou, Fengming
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Read Online
- Indazole kinase inhibitor and applications thereof
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The present invention relates to a kinase inhibitor, which comprises a compound represented by a formula (I), or a pharmaceutically acceptable salt, a solvate, an ester, an acid, a metabolite or a prodrug thereof. The invention also relates to a pharmaceu
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Paragraph 0138-0140
(2020/06/02)
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- Synthesis, biological evaluation and molecular modeling study of some new thiazolodiazepine analogs as CNS active agents
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New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 3), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3. Compounds 15 (0.78 mmol/kg) and 20 (0.39 mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38 mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABAA. Superposition, flexible alignment and surface mapping of 15, 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants.
- Al-Rashood, Sarah T.A.,Hassan, Ghada S.,El-Messery, Shahenda M.,El-Taher, Kamal E.H.,Hefnawy, Mohamed M.,Al-Omar, Mahmmed A.,El-Subbagh, Hussein I.
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supporting information
p. 445 - 453
(2016/01/09)
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- INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE
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The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of variou
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Page/Page column 38
(2008/06/13)
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- BICYCLIC PYRIMIDINONES AND USES THEREOF
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The present invention provides a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment or prophylaxis of a viral infection in a subject comprising administering to said subject an effective amount of a compound of Formula I or a pharmaceutically acceptable derivative, salt or prodrug thereof. A pharmaceutical composition or medicament comprising a compoundof Formula I is also provided.
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Page/Page column 99
(2008/12/06)
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- ORGANIC COMPOUNDS
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The present invention concerns a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, wherein the groups Ri- Rs are defined in the description, to compositions and use of the compounds in the treatment of diseases ameloriate
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Page/Page column 10
(2008/06/13)
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- QUINOLONES USEFUL AS INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
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The present invention relates to novel quinolones of Formula I that inhibit inducible NOS synthase together with methods of synthesizing and using the compounds including methods for inhibiting or modulating nitric oxide synthesis and/or lowering nitric oxide levels in a patient by administering the compounds for the treatment of disease.
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Page/Page column 74
(2008/12/06)
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- THIAZOLE DERIVATIVES AND USE THEREOF
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The present invention is related to thiazole derivatives of Formula (I) in particular for the treatment and/or prophylaxis of autoimmune disorders and/or inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, bacterial or viral infect
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Page/Page column 61-62
(2008/06/13)
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- Vilsmeier Haack reaction of substituted 2-acetamidothiazole derivatives and their antimicrobial activity
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Vilsmeier Haack (VMH) reaction of 2-acetamidothiazole having carbethoxy group at C-4 affords the unexpected N-formylated product, which is followed by deacetylation. The same reaction with substituents other than carbethoxy group at C-4 position (viz CHs
- Koti,Kolavi,Hegde,Khazi
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p. 1900 - 1904
(2007/10/03)
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- 5-PHENYLTHIAZOLE DERIVATIVES AND USE AS PI3 KINASE INHIBITORS
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Compounds of Formula I in free or salt form, wherein R1,R2,R3,R4, and R5, have the meanings as indicated in the specification, are useful for treating diseases mediated by phosphatidylinositol 3-kinase. Pharmaceutical compositions that contain the compounds and processes for preparing the compounds are also described.
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Page/Page column 41
(2010/02/07)
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- Synthetic Study Directed Toward Novel Multi-Linked Heterocycles
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2-Amino-4-(1-methylindol-3-yl)thiazole (11c) has a characteristic nucleophilic nature at the 5-position and add to the 4-position of acetylpyridinium acetate (13) producing 2-acetylamino-5-(1-acetyl-1,4-dihydropyridin-4-yl)-4-(1-methylindol-3-yl)-thiazole (1c).Its structure was established by X-ray single crystallographic analysis.Applying the results, simple syntheses of the related tris- (1a-b and 2-8) and tetrakislinked heterocycles (9) were achieved.
- Somei, Masanori,Yamada, Yoshikazu,Kitagawa, Keiichi,Sugaya, Katsuko,Tomita, Yayoi,et. al
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p. 434 - 438
(2007/10/03)
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