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Dihydrobenzofuranyl-phenylpiperazines as vasodilating agents: synthesis and evaluation of LINS01005 analogs

Grant number: 17/05441-6
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2017
Effective date (End): December 31, 2018
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:João Paulo dos Santos Fernandes
Grantee:Gustavo Ariel Borges Fernandes
Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil


Hypertension is an important public health issue due to its high socioeconomic cost. Therefore, the search for novel antihypertensive agents is still a continuous goal in drug design and development. Since 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]-4-phenylpiperazine molecules have already been reported as antihypertensive agents in the literature, a preliminary study of the vasoactive activity of the molecule LINS01005 in isolated rat aortic rings demonstrated potent vasodilatory activity. Considering the therapeutic potential of vasodilator molecules, and the knowledge of structure-activity relationships is fundamental to guide the rational design of new bioactive compounds, this project aims to systematically evaluate the vasodilatory potency of 5-substituted derivatives of LINS01005. Such compounds will be prepared starting from the 4-substituted phenols, which will be allyled, isomerized and cyclized to obtain the compounds of interest, by methodologies already established in our group. Vasodilator activity studies will be performed on isolated aortic rings from Wistar and SHR rats, previously contracted with norepinephrine, in the presence and absence of endothelium, using the protocol already established by the Nephrology Discipline. Dose-response curves will be performed for the prepared compounds, and the blockade of the classical signaling pathways involved in the vasodilatory activity are intended to be performed. (AU)

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Scientific publications (6)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CORREA, MICHELLE F.; REINER, DAVID; FERNANDES, GUSTAVO A. B.; VARELA, MARINA T.; ARANHA, CECILIA M. S. Q.; STARK, HOLGER; FERNANDES, JOAO PAULO S.. Profiling of LINS01 compounds at human dopamine D-2 and D-3 receptors. JOURNAL OF CHEMICAL SCIENCES, v. 132, n. 1, . (17/05441-6, 18/03918-2, 18/04488-1, 16/25028-3)
CORREA, MICHELLE FIDELIS; RAMOS BARBOSA, ALEFE JHONATAS; BORGES FERNANDES, GUSTAVO ARIEL; BAKER, JILLIAN G.; DOS SANTOS FERNANDES, JOAO PAULO. Pharmacological and SAR analysis of the LINS01 compounds at the human histamine H-1, H-2, and H-3 receptors. CHEMICAL BIOLOGY & DRUG DESIGN, v. 93, n. 1, p. 89-95, . (16/25028-3, 17/05441-6, 16/23139-2)
BALBINO, A. M.; LIMA, L. J. S.; FERNANDES, G. A. B.; CORREA, M. F.; LANDGRAF, M. A. V.; FERNANDES, J. P. S.; LANDGRAF, R. G.. MODULATORY EFFECTS OF HISTAMINE H3R/H4R ANTAGONISTS LINS01005 AND LINS01007 ON THE INFLAMMATORY RESPONSE IN MURINE ASTHMA MODEL. Inflammation Research, v. 68, p. 1-pg., . (12/51104-8, 17/02042-3, 16/23139-2, 16/25028-3, 17/05441-6)
CORREA, M. F.; SILVA, A. B.; PENOMIAN, L.; SIMOES, S. C.; FERNANDES, G. A. B.; ARANHA, C. M. S. Q.; VARELA, M. T.; COSTA-NETO, C. M.; FERNANDES, J. P. S.. EVALUATION AND SAR STUDY OF NOVEL SUBSTITUTED (DIHYDRO)BENZOFURANYL-PIPERAZINES AS HISTAMINE H3R AND H4R LIGANDS. Inflammation Research, v. 68, p. 1-pg., . (18/04488-1, 18/03918-2, 16/23139-2, 16/25028-3, 17/05441-6)
CORRE, MICHELLE F.; BALICO-SILVA, ANDRE L.; KISS, DORA J.; FERNANDES, GUSTAVO A. B.; MARASCHIN, JHONATAN C.; PARREIRAS-E-SILVA, LUCAS T.; VARELA, MARINA T.; SIMOES, SARAH C.; BOUVIER, MICHEL; KESERU, GYORGY M.; et al. Novel potent (dihydro)benzofuranyl piperazines as human histamine receptor ligands - Functional characterization and modeling studies on H-3 and H(4 )receptors. Bioorganic & Medicinal Chemistry, v. 30, . (16/24120-3, 17/05441-6, 12/20148-0, 16/25028-3, 18/03918-2, 18/00153-5, 16/08920-0, 16/23139-2)
GINOZA, MILTON; FERNANDES, GUSTAVO A. B.; CORREA, MICHELLE F.; FERNANDES, JOAO PAULO S.. Novel potent vasodilating agents: Evaluation of the activity and potency of LINS01005 and derivatives in rat aorta. European Journal of Pharmaceutical Sciences, v. 143, . (17/05441-6, 16/23139-2, 16/25028-3)

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