ALK5 kinase inhibitory activity and synthesis of
2,3,4-substituted
5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

J 2017

ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

ŘEZNÍČKOVÁ, Eva, Lukáš TENORA, Pavlína POSPÍŠILOVÁ, Juraj GALETA, Radek JORDA et. al.

Basic information

Original name

ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles

Authors

ŘEZNÍČKOVÁ, Eva (203 Czech Republic), Lukáš TENORA (203 Czech Republic, belonging to the institution), Pavlína POSPÍŠILOVÁ (203 Czech Republic), Juraj GALETA (703 Slovakia, belonging to the institution), Radek JORDA (203 Czech Republic), Karel BERKA (203 Czech Republic), Pavel MAJER (203 Czech Republic), Milan POTÁČEK (203 Czech Republic, belonging to the institution) and Vladimír KRYŠTOF (203 Czech Republic)

Edition

European Journal of Medicinal Chemistry, 2017, 0223-5234

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10401 Organic chemistry

Country of publisher

France

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 4.816

RIV identification code

RIV/00216224:14310/17:00096184

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1016/j.ejmech.2017.01.018

UT WoS

000397172800051

Keywords in English

Transforming growth factor beta receptor I; Protein kinase; Inhibitor; Substituted pyrrolo[1.2-b]pyrazoles

Abstract

V originále

A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFb and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.

Links

LM2015047, research and development project

Name: Česká národní infrastruktura pro biologická data (Acronym: ELIXIR-CZ)

Investor: Ministry of Education, Youth and Sports of the CR, Czech National Infrastructure for Biological Data

Citovat

ŘEZNÍČKOVÁ, Eva, Lukáš TENORA, Pavlína POSPÍŠILOVÁ, Juraj GALETA, Radek JORDA, Karel BERKA, Pavel MAJER, Milan POTÁČEK and Vladimír KRYŠTOF. ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. European Journal of Medicinal Chemistry. 2017, vol. 2017, No 127, p. 632-642. ISSN 0223-5234. Available from: https://dx.doi.org/10.1016/j.ejmech.2017.01.018.

@article{1373192,
   author = {Řezníčková, Eva and Tenora, Lukáš and Pospíšilová, Pavlína and Galeta, Juraj and Jorda, Radek and Berka, Karel and Majer, Pavel and Potáček, Milan and Kryštof, Vladimír},
   article_number = {127},
   doi = {http://dx.doi.org/10.1016/j.ejmech.2017.01.018},
   keywords = {Transforming growth factor beta receptor I; Protein kinase; Inhibitor; Substituted pyrrolo[1.2-b]pyrazoles},
   language = {eng},
   issn = {0223-5234},
   journal = {European Journal of Medicinal Chemistry},
   title = {ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles},
   url = {http://dx.doi.org/10.1016/j.ejmech.2017.01.018},
   volume = {2017},
   year = {2017}
}

TY  - JOUR
ID  - 1373192
AU  - Řezníčková, Eva - Tenora, Lukáš - Pospíšilová, Pavlína - Galeta, Juraj - Jorda, Radek - Berka, Karel - Majer, Pavel - Potáček, Milan - Kryštof, Vladimír
PY  - 2017
TI  - ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles
JF  - European Journal of Medicinal Chemistry
VL  - 2017
IS  - 127
SP  - 632-642
EP  - 632-642
SN  - 02235234
KW  - Transforming growth factor beta receptor I
KW  - Protein kinase
KW  - Inhibitor
KW  - Substituted pyrrolo[1.2-b]pyrazoles
UR  - http://dx.doi.org/10.1016/j.ejmech.2017.01.018
L2  - http://dx.doi.org/10.1016/j.ejmech.2017.01.018
N2  - A series of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles (DPPs) was synthesized and evaluated for their ALK5 inhibition activity. The most potent compounds displayed submicromolar IC50 values for ALK5. Preliminary profiling of one of the most active compounds in a panel of 50 protein kinases revealed its selectivity for ALK5. In cells, the compounds caused dose-dependent dephosphorylation of SMAD2, a well-established substrate of ALK5. In addition, the compounds blocked translocation of SMAD2/3 to nuclei of cells stimulated with TGFb and the protein remained predominantly in cytoplasm, further confirming their molecular target. Therefore, novel DPP derivatives proved to be active as ALK5 inhibitors.
ER  -

ŘEZNÍČKOVÁ, Eva, Lukáš TENORA, Pavlína POSPÍŠILOVÁ, Juraj GALETA, Radek JORDA, Karel BERKA, Pavel MAJER, Milan POTÁČEK and Vladimír KRYŠTOF. ALK5 kinase inhibitory activity and synthesis of 2,3,4-substituted 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles. \textit{European Journal of Medicinal Chemistry}. 2017, vol.~2017, No~127, p.~632-642. ISSN~0223-5234. Available from: https://dx.doi.org/10.1016/j.ejmech.2017.01.018.

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