Docking, synthesis and pharmacological activity of novel urea-derivatives designed as p38 MAPK inhibitors.
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.
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.
Raquel
R
de Oliveira Lopes
Nelilma Correia
NC
Romeiro
Cleverton Kleiton F
CK
de Lima
Leandro
L
Louback  da Silva
Ana Luisa Palhares
AL
de Miranda
Paulo Gustavo B D
PG
Nascimento
Fernando Q
FQ
Cunha
Eliezer J
EJ
Barreiro
Lídia Moreira
LM
Lima
D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D059225:Nociception / Q000187:drug effects; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D002351:Carrageenan; D048051:p38 Mitogen-Activated Protein Kinases