Premium
LASSBio‐1829 Hydrochloride: Development of a New Orally Active N ‐Acylhydrazone IKK2 Inhibitor with Anti‐inflammatory Properties
Author(s) -
Guedes Isabella A.,
Freitas Rosana H. C. N.,
Cordeiro Natália M.,
Nascimento Thaís S. do,
Valerio Tayna S.,
Fernandes Patrícia D.,
Dardenne Laurent E.,
Fraga Carlos A. M.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500266
Subject(s) - hydrochloride , chemistry , pharmacology , potency , in vivo , stereochemistry , drug , in vitro , medicine , biochemistry , biology , microbiology and biotechnology
Inhibitor of nuclear factor κB kinase 2 (IKK2) is suggested to be a potential target for the development of novel anti‐inflammatory and anticancer drugs. In this work, we applied structure‐based drug design to improve the potency of the inhibitor ( E )‐ N ′‐(4‐nitrobenzylidene)‐2‐naphthohydrazide (LASSBio‐1524, 1 a : IC 50 =20 μ m ). The molecular model built for IKK2 together with the docking methodology employed were able to provide important and consistent information with respect to the structural and chemical inhibitor characteristics that may confer potency to IKK2 inhibitors, providing important guidelines for the development of a new N ‐acylhydrazone (NAH) derivative. ( E )‐ N ′‐(4‐(1 H ‐pyrrolo[2,3‐ b ]pyridin‐4‐yl)benzylidene)‐2‐naphthohydrazide hydrochloride (LASSBio‐1829 hydrochloride, 10 ) is a 7‐azaindole NAH able to inhibit IKK2 with an IC 50 value of 3.8 μ m . LASSBio‐1829 hydrochloride was found to be active in several pharmacological inflammation tests in vivo, showing its potential as an anti‐inflammatory prototype.