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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Ginoza, Milton [1] ; Fernandes, Gustavo A. B. [1] ; Correa, Michelle F. [1] ; Fernandes, Joao Paulo S. [1]
Total Authors: 4
Affiliation:
[1] Univ Fed Sao Paulo, Dept Ciencias Farmaceut, Rua Sao Nicolau 210, BR-09913030 Diadema, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: European Journal of Pharmaceutical Sciences; v. 143, FEB 15 2020.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 17/05441-6 - Dihydrobenzofuranyl-phenylpiperazines as vasodilating agents: synthesis and evaluation of LINS01005 analogs
Grantee:Gustavo Ariel Borges Fernandes
Support Opportunities: Scholarships in Brazil - Scientific Initiation
FAPESP's process: 16/23139-2 - Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach
Grantee:Michelle Fidelis Corrêa
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
Grantee:João Paulo dos Santos Fernandes
Support Opportunities: Regular Research Grants