- Design and synthesis of 1H-pyrazolo[3,4-b]pyridines targeting mitogen-activated protein kinase kinase 4 (MKK4) - A promising target for liver regeneration
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Currently, the therapeutic options for treatment of liver failure are very limited. As mitogen-activated protein kinase kinase 4 (MKK4) has recently been identified by in vivo RNAi experiments to be a major regulator in hepatocyte regeneration, we pursued the development of a small molecule targeting this protein kinase. Starting from the approved BRAFV600E inhibitor vemurafenib (8), that showed a high off-target affinity to MKK4 in an initial screening, we followed a scaffold-hopping approach, changing the core heterocycle from 1H-pyrrolo[2,3-b]pyridine to 1H-pyrazolo[2,3-b]pyridine (10). Affinity to MKK4 could be conserved while the selectivity against off-target protein kinases was slightly improved. Further modifications led to 58 and 59 showing high affinity to MKK4 in the low nanomolar range and excellent selectivity profile from mandatory multiparameter-optimization for the essential anti-targets (MKK7, JNK1) and off-targets (BRAF, MAP4K5, ZAK) in the MKK4 pathway. Herein we report the first selective MKK4 inhibitors in this class.
- Pfaffenrot, Bent,Kl?vekorn, Philip,Juchum, Michael,Selig, Roland,Albrecht, Wolfgang,Zender, Lars,Laufer, Stefan A.
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supporting information
(2021/04/05)
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- PROTEIN KINASE MKK4 INHIBITORS FOR PROMOTING LIVER REGENERATION OR REDUCING OR PREVENTING HEPATOCYTE DEATH
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The invention relates to pyrazolo-pyridine compounds which inhibit mitogen-activated protein kinase kinase 4 (MKK4) and in particular, selectively inhibit MKK4 over protein kinases JNK1 and MKK7. The compounds are useful for promoting liver regeneration or reducing or preventing hepatocyte death. They are further useful for treating osteoarthritis or rheumatoid arthritis, or CNS-related diseases.
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Page/Page column 75
(2019/08/26)
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- TRICYCLIC ALKYNES THAT INTERACT WITH GLUCOKINASE REGULATORY PROTEIN
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The present invention relates to tricyclic alkyne compounds of formula I that interact with glucokinase regulatory protein. In addition, the present invention relates to methods of treating type 2 diabetes, and other diseases and/or conditions where gluco
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Page/Page column 143-144
(2014/03/25)
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- Copper-catalyzed trifluoromethylation and cyclization of aromatic-sulfonyl-group-tethered alkenes for the construction of 1,2-benzothiazinane dioxide type compounds
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A multi-talented system: An efficient copper-catalyzed tandem trifluoromethylation/annulation of an electron-deficient aromatic ring has been developed. This method provides a powerful and straightforward way to synthesize trifluoromethylated 1,2-benzothiazinane dioxides under mild conditions (see scheme). The mechanism was investigated by a series of kinetic experiments and isotopic labeling studies.
- Dong, Xiang,Sang, Rui,Wang, Qiang,Tang, Xiang-Ying,Shi, Min
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supporting information
p. 16910 - 16915
(2014/01/06)
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- ARYL SULFONAMIDES USEFUL FOR MODULATION OF THE PROGESTERONE RECEPTOR
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In one embodiment, compounds of the following structure are described, wherein R1 to R7 are described herein. Also provided are methods for preparing these compounds and methods of contraception; treating or preventing fibroids; trea
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Page/Page column 9
(2008/12/08)
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