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Discovery of naphthyl‐ N ‐acylhydrazone p38α MAPK inhibitors with in vivo anti‐inflammatory and anti‐TNF‐α activity
Author(s) -
Freitas Rosana H. C. N.,
Cordeiro Natália M.,
Carvalho Patrícia R.,
Alves Marina A.,
Guedes Isabella A.,
Valerio Tayna S.,
Dardenne Laurent E.,
Lima Lídia M.,
Barreiro Eliezer J.,
Fernandes Patrícia D.,
Fraga Carlos A. M.
Publication year - 2018
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13085
Subject(s) - in vivo , p38 mitogen activated protein kinases , kinase , mapk/erk pathway , pharmacology , in vitro , protein kinase a , chemistry , serine , docking (animal) , biochemistry , medicine , phosphorylation , biology , microbiology and biotechnology , nursing
Protein kinases constitute attractive therapeutic targets for development of new prototypes to treat different chronic diseases. Several available drugs, like tinibs, are tyrosine kinase inhibitors; meanwhile, inhibitors of serine/threonine kinases, such as mitogen‐activated protein kinase (MAPK), are still trying to overcome some problems in one of the steps of clinical development to become drugs. So, here we reported the synthesis, the in vitro kinase inhibitory profile, docking studies, and the evaluation of anti‐inflammatory profile of new naphthyl‐ N ‐acylhydrazone derivatives using animal models. Although all tested compounds ( 3a–d ) have been characterized as p38α MAPK inhibitors and have showed in vivo anti‐inflammatory action, LASSBio‐1824 ( 3b ) presented the best performance as p38α MAPK inhibitor, with IC 50 = 4.45 μ m , and also demonstrated to be the most promising anti‐inflammatory prototype, with good in vivo anti‐TNF‐α profile after oral administration.