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

• Published in: European journal of medicinal chemistry 2012-08, Vol.54, p.264-271
• Main Authors: de Oliveira Lopes, Raquel, Romeiro, Nelilma Correia, de Lima, Cleverton Kleiton F., Louback da Silva, Leandro, Palhares de Miranda, Ana Luisa, Nascimento, Paulo Gustavo B.D., Cunha, Fernando Q., Barreiro, Eliezer J., Lima, Lídia Moreira
• Format: Article
• Language: English
• Subjects: Analgesic; Animals; Anti-inflammatory; Arthritis; Biological and medical sciences; Carrageenan - pharmacology; Docking; Dose-Response Relationship, Drug; Drug Design; Edema - chemically induced; Edema - drug therapy; Female; Male; Medical sciences; Mice; Miscellaneous; Molecular Docking Simulation; Nociception - drug effects; p38 MAPK; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - chemistry; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology. Drug treatments; Protein Conformation; Protein Kinase Inhibitors - analogs & derivatives; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha - biosynthesis; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - metabolism; Urea - pharmacology
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.05.006

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. The docking, synthesis and pharmacological activity of novel urea-derivatives (4a–e) designed as p38 MAPK inhibitors are reported. Compound 4e (LASSBio-998) was demonstrated to be a new antiarthritis prototype. [Display omitted] ► The ability of urea-derivatives (4a–e) to be recognized by p38 MAPK was determined by docking studies. ► Compound 4e showed a better score value compared to the prototype GK-00687. ► Anti-inflammatory and analgesic activities of compound 4e were demonstrated. ► Compound 4e is a weak inhibitor of TNF-alfa production and p38 MAPK.