Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta

Autor(es)

Ginoza, Milton ^[1] ; Fernandes, Gustavo A. B. ^[1] ; Correa, Michelle F. ^[1] ; Fernandes, Joao Paulo S. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: European Journal of Pharmaceutical Sciences; v. 143, FEB 15 2020.
• Citações Web of Science: 0

Resumo

Cardiovascular diseases (CVDs) present high prevalence rates in the current world. It is estimated that approximately one-third of the global deaths are related to CVD5, and thus there is still a need for novel drugs to treat these disorders. We serendipitously discovered that LINS01005 (5a) is a potent vasodilating agent in rat aorta, and therefore a set of analogues were evaluated for the vasodilating potency in Wistar and SHR rat thoracic aorta precontracted with norepinephrine, with endothelium intact (E+) or denuded (E-) aortic rings. Compounds 5a and 5b were the most potent, showing submicromolar potency for endothelium intact vessels (EC50 853 and 941 nM, respectively) and micromolar values for E- vessels (EC50 2.4 and 7.1 pM, respectively). These compounds were indeed significantly more potent vasodilating agents in SHR-derived aortic rings (p < 0.001), showing nanomolar potency for 5a {[}EC50 2.4 nM (E+) 9.0 nM (E-)] and 5b {[}EC50 20 nM (E+) 2.1 mu M (E-)]. SAR analysis though PCA and HCA were performed, suggesting that N-phenylpiperazine is essential to the activity, while increasing volume in the substituted aromatic moiety is detrimental to the potency. This is the first report of the vasodilating properties of such compounds, and studies regarding the mechanism of action are in progress in our group. (AU)

• Processo FAPESP: 17/05441-6 - Diidrobenzofuranil-fenilpiperazinas como agentes vasodilatadores: síntese e avaliação de análogos do LINS01005
• Beneficiário: Gustavo Ariel Borges Fernandes
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 16/23139-2 - Síntese e avaliação biológica de compostos da série LINS01 como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: Michelle Fidelis Corrêa
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 16/25028-3 - Anti-histamínicos H3R/H4R como agentes pró-cognitivos: uma abordagem multialvo
• Beneficiário: João Paulo dos Santos Fernandes
• Modalidade de apoio: Auxílio à Pesquisa - Regular