Design, Synthesis, and Structure-Activity Relationships of Biaryl Anilines as Subtype-Selective PPAR-alpha Agonists.
Journal
ACS medicinal chemistry letters
ISSN: 1948-5875
Titre abrégé: ACS Med Chem Lett
Pays: United States
ID NLM: 101521073
Informations de publication
Date de publication:
08 Jun 2023
08 Jun 2023
Historique:
received:
16
02
2023
accepted:
16
05
2023
pmc-release:
08
06
2024
medline:
14
6
2023
pubmed:
14
6
2023
entrez:
14
6
2023
Statut:
epublish
Résumé
The role of peroxisome proliferator-activated receptor alpha (PPARα) in retinal biology is clarifying, and evidence demonstrates that novel PPARα agonists hold promising therapeutic utility for diseases like diabetic retinopathy and age-related macular degeneration. Herein, we disclose the design and initial structure-activity relationships for a new biaryl aniline PPARα agonistic chemotype. Notably, this series exhibits subtype selectivity for PPARα over other isoforms, a phenomenon postulated to be due to the unique benzoic acid headgroup. This biphenyl aniline series is sensitive to B-ring functionalization but allows isosteric replacement, and provides an opportunity for C-ring extension. From this series,
Identifiants
pubmed: 37312852
doi: 10.1021/acsmedchemlett.3c00056
pmc: PMC10258832
doi:
Types de publication
Journal Article
Langues
eng
Pagination
766-776Informations de copyright
© 2023 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): A.S.D. and J.X.M. are co-founders of Excitant Therapeutics.
Références
Diabetes. 2013 Dec;62(12):3968-75
pubmed: 24264394
J Med Chem. 2012 May 10;55(9):4027-61
pubmed: 22260081
Biochem Biophys Res Commun. 2018 May 5;499(2):239-245
pubmed: 29567478
Chem Sci. 2022 Jan 19;13(9):2744-2752
pubmed: 35340861
N Engl J Med. 2010 Jul 15;363(3):233-44
pubmed: 20587587
Int J Biochem Cell Biol. 2010 Jan;42(1):5-12
pubmed: 19836461
BMC Biol. 2017 Nov 28;15(1):113
pubmed: 29183319
Elife. 2018 Dec 21;7:
pubmed: 30575522
Annu Rev Med. 2002;53:409-35
pubmed: 11818483
Nat Rev Drug Discov. 2014 Feb;13(2):105-21
pubmed: 24481311
Proc Natl Acad Sci U S A. 2013 Sep 17;110(38):15401-6
pubmed: 24003152
J Med Chem. 2010 Apr 8;53(7):2854-64
pubmed: 20218621
Lancet. 2007 Nov 17;370(9600):1687-97
pubmed: 17988728
Prog Retin Eye Res. 2015 Sep;48:160-80
pubmed: 25936649
PLoS One. 2012;7(5):e33643
pubmed: 22606221
Bioorg Med Chem Lett. 2018 Sep 1;28(16):2717-2722
pubmed: 29628329
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7355-9
pubmed: 8041794
World J Diabetes. 2015 Apr 15;6(3):489-99
pubmed: 25897358
J Diabetes Res. 2016;2016:3789217
pubmed: 26881246
Diabetes. 2013 Jan;62(1):261-72
pubmed: 23043158
J Med Chem. 2020 Mar 26;63(6):2854-2876
pubmed: 32096640
Bioorg Med Chem Lett. 2001 May 7;11(9):1225-7
pubmed: 11354382