Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1 H -imidazoles as ALK5 inhibitors.

Tytuł:: Synthesis, biological evaluation and molecular modelling of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1 H -imidazoles as ALK5 inhibitors.
Autorzy:: Park MS; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Park HJ; School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
An YJ; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Choi JH; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Cha G; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Lee HJ; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Park SJ; School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.
Dewang PM; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Kim DK; Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, South Korea.
Źródło:: Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2020 Dec; Vol. 35 (1), pp. 702-712.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
MeSH Terms:: Imidazoles/*pharmacology
Protein Kinase Inhibitors/*pharmacology
Receptor, Transforming Growth Factor-beta Type I/*antagonists & inhibitors
Caco-2 Cells ; Cell Line ; Dose-Response Relationship, Drug ; Humans ; Imidazoles/chemical synthesis ; Imidazoles/chemistry ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Receptor, Transforming Growth Factor-beta Type I/metabolism ; Structure-Activity Relationship
References:: Eur J Cancer. 2003 Mar;39(4):454-61. (PMID: 12751375)
Gastrointest Endosc. 2017 Jul;86(1):219-228. (PMID: 28137596)
Cancer Sci. 2016 Feb;107(2):140-8. (PMID: 26583567)
Bioorg Med Chem Lett. 2004 Jul 5;14(13):3581-4. (PMID: 15177479)
J Med Chem. 2004 Aug 26;47(18):4494-506. (PMID: 15317461)
Nat Rev Cancer. 2006 Jul;6(7):506-20. (PMID: 16794634)
EMBO Mol Med. 2013 Nov;5(11):1720-39. (PMID: 24127404)
Cell Mol Life Sci. 2015 May;72(10):2023-39. (PMID: 25487606)
J Urol. 1996 Sep;156(3):953-7. (PMID: 8709371)
Org Lett. 2013 Apr 5;15(7):1536-9. (PMID: 23489071)
Mol Pharmacol. 2004 Mar;65(3):744-52. (PMID: 14978253)
J Comput Aided Mol Des. 2012 Jun;26(6):687-99. (PMID: 22569590)
Eur J Med Chem. 2017 Feb 15;127:632-642. (PMID: 28135685)
Surgery. 2018 Nov;164(5):1100-1108. (PMID: 30172565)
Eur J Med Chem. 2015 Mar 26;93:599-613. (PMID: 25234355)
Int J Biol Markers. 2012 Jan-Mar;27(1):53-9. (PMID: 22020368)
Liver Int. 2019 Aug;39(8):1468-1477. (PMID: 30963691)
Mol Cancer Ther. 2014 Jul;13(7):1704-16. (PMID: 24817629)
Braz J Med Biol Res. 2016 Jul 25;49(8):. (PMID: 27464025)
Eur J Med Chem. 2009 Feb;44(2):568-76. (PMID: 18467006)
Clin Cancer Res. 2015 Aug 15;21(16):3678-84. (PMID: 25977342)
J Med Chem. 2014 May 22;57(10):4213-38. (PMID: 24786585)
J Urol. 1999 Jan;161(1):182-7. (PMID: 10037394)
Cell Physiol Biochem. 2016;38(2):571-88. (PMID: 26845171)
Gastroenterology. 1996 Feb;110(2):375-82. (PMID: 8566583)
PLoS One. 2018 Feb 15;13(2):e0192430. (PMID: 29447198)
Immunity. 2019 Apr 16;50(4):924-940. (PMID: 30995507)
Cancer. 2001 Dec 15;92(12):2985-92. (PMID: 11753975)
Drug Des Devel Ther. 2015 Aug 10;9:4479-99. (PMID: 26309397)
J Med Chem. 2007 Jun 28;50(13):3143-7. (PMID: 17552507)
Nat Rev Cancer. 2013 Nov;13(11):788-99. (PMID: 24132110)
Br J Cancer. 1998 May;77(9):1492-4. (PMID: 9652767)
J Clin Oncol. 2001 Jun 1;19(11):2856-64. (PMID: 11387358)
Chem Biol. 1998 Jun;5(6):321-8. (PMID: 9653550)
Contributed Indexing:: Keywords: 2,4-Disubstituted-5-(6-alkylpyridin-2-yl)-1H-imidazoles; ALK5 inhibition; cancer immunotherapeutic agent; docking
Substance Nomenclature:: 0 (Imidazoles)
0 (Protein Kinase Inhibitors)
EC 2.7.11.30 (Receptor, Transforming Growth Factor-beta Type I)
EC 2.7.11.30 (TGFBR1 protein, human)
Entry Date(s):: Date Created: 20200314 Date Completed: 20201027 Latest Revision: 20210507
Update Code:: 20240105
PubMed Central ID:: PMC7144182
DOI:: 10.1080/14756366.2020.1734799
PMID:: 32164459
: Czasopismo naukowe

Pełny tekst

A series of 2,4-disubstituted-5-(6-alkylpyridin-2-yl)-1 H -imidazoles, 7a-c , 11a-h , and 16a-h has been synthesised and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Incorporation of a quinoxalin-6-yl moiety and a methylene linker at the 4- and 2-position of the imidazole ring, respectively, and a m- CONH 2 substituent in the phenyl ring generated a highly potent and selective ALK5 inhibitor 11e . Docking model of ALK5 in complex with 11e showed that it fitted well in the ATP-binding pocket with favourable interactions.

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