Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors.

Autor: de Oliveira Lopes R; LASSBio - Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, P. O. Box 68024, 21944-971 Rio de Janeiro, RJ, Brazil., Romeiro NC, de Lima CK, Louback da Silva L, de Miranda AL, Nascimento PG, Cunha FQ, Barreiro EJ, Lima LM
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2012 Aug; Vol. 54, pp. 264-71. Date of Electronic Publication: 2012 May 14.
DOI: 10.1016/j.ejmech.2012.05.006
Abstrakt: p38 mitogen-activated protein kinase (p38 MAPK) is an important signal transducing enzyme involved in many cellular regulations, including signaling pathways, pain and inflammation. Several p38 MAPK inhibitors have been developed as drug candidates to treatment of autoimmune disorders, such as rheumatoid arthritis. In this paper we reported the docking, synthesis and pharmacological activity of novel urea-derivatives (4a-e) designed as p38 MAPK inhibitors. These derivatives presented good theoretical affinity to the target p38 MAPK, standing out compound 4e (LASSBio-998), which showed a better score value compared to the prototype GK-00687. This compound was able to reduce in vitro TNF-α production and was orally active in a hypernociceptive murine model sensible to p38 MAPK inhibitors. Otherwise, compound 4e presented a dose-dependent analgesic effect in a model of antigen (mBSA)-induced arthritis and anti-inflammatory profile in carrageenan induced paw edema, indicating its potential as a new antiarthritis prototype.
(Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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