Title:Synthesis, Aqueous Solubility, Metabolic Stability and Pharmacological Profile of Simplified Urea Derivatives
VOLUME: 15 ISSUE: 7
Author(s):Raquel de Oliveira Lopes, Marina Amaral Alves, Roberta Olmo Pinheiro, Cristina Setim Freitas, Fernando Q. Cunha, Eliezer J. Barreiro* and Lídia Moreira Lima*
Affiliation:Pos-graduacao em Quimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Pos-graduacao em Quimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Laboratorio de Hanseniase, Instituto Oswaldo Cruz, Fundacao Oswaldo Cruz, Rio de Janeiro, RJ, Laboratorio de Dor e Inflamacao, Departamento de Farmacologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, SP, Laboratorio de Dor e Inflamacao, Departamento de Farmacologia, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, SP, Pos-graduacao em Quimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Pos-graduacao em Quimica, Instituto de Quimica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ
Keywords:p38 MAPK, metabolic stability, urea derivatives, antihipernociceptive activity, antinociceptive activity, THP-1
cells.
Abstract:Objective: In this paper, the synthesis, plasma and microsomal stability, and in vitro and
in vivo pharmacological profile of urea derivatives (6a-d) designed by molecular simplification on
prototype LASSBio-998 are described.
Methodology: Compounds were synthesiized exploring condensation of amine derivatives with
cyclohexylisocyanate. Plasma and microsomal stabilities were analyzed by HPLC. Chemical stability
was investigated at pH 1.2 and 7.4. Aqueous solubility was determined using UV-spectroscopy.
The in vivo activity was determined using hypernociception induced by carrageenan and capsaicininduced
nociception models.
Results: Among the synthesized compounds, LASSBio-1495(6b) stood out displaying antihipernociceptive
and antinociceptive activities by oral administration; it inhibited pp38 expression in PMA
- differentiated THP-1 cells and TNFα production induced by LPS; inhibited p38α activity, albeit
in low potency (IC50 = 60 ± 4.5 µM); and showed better solubility and metabolic stability than the
original prototype LASSBio-998.
Conclusion: The simplified urea derivatives 6a-d showed improvement in their solubility and stability
profile, displayed potent anti-TNFα activity through mechanism that is probably independent
of p38α inhibition, and exhibited antihypernociceptive and antinociceptive effects by oral administration.
