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.

Základní údaje

Originální název

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

Autoři

ŘEZNÍČKOVÁ, Eva (203 Česká republika), Lukáš TENORA (203 Česká republika, domácí), Pavlína POSPÍŠILOVÁ (203 Česká republika), Juraj GALETA (703 Slovensko, domácí), Radek JORDA (203 Česká republika), Karel BERKA (203 Česká republika), Pavel MAJER (203 Česká republika), Milan POTÁČEK (203 Česká republika, domácí) a Vladimír KRYŠTOF (203 Česká republika)

Vydání

European Journal of Medicinal Chemistry, 2017, 0223-5234

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10401 Organic chemistry

Stát vydavatele

Francie

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.816

Kód RIV

RIV/00216224:14310/17:00096184

Organizační jednotka

Přírodovědecká fakulta

DOI

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

UT WoS

000397172800051

Klíčová slova anglicky

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

Štítky

NZ, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 23. 4. 2020 15:36, Mgr. Marie Šípková, DiS.

Anotace

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.

Návaznosti

LM2015047, projekt VaV

Název: Česká národní infrastruktura pro biologická data (Akronym: ELIXIR-CZ)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, Česká národní infrastruktura pro biologická data

Citovat

ŘEZNÍČKOVÁ, Eva, Lukáš TENORA, Pavlína POSPÍŠILOVÁ, Juraj GALETA, Radek JORDA, Karel BERKA, Pavel MAJER, Milan POTÁČEK a 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, roč. 2017, č. 127, s. 632-642. ISSN 0223-5234. Dostupné z: 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 a 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, roč.~2017, č.~127, s.~632-642. ISSN~0223-5234. Dostupné z: https://dx.doi.org/10.1016/j.ejmech.2017.01.018.

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