19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension

Rambabu Dakarapu; Ramu Errabelli; Vijaya L. Manthati; Adeniyi Michael Adebesin; Deb K. Barma; Deepan Barma; Victor Garcia; Fan Zhang; Michal Laniado Schwartzman; John R. Falck

doi:10.1016/j.bmcl.2019.08.020

19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension

Rambabu Dakarapu, Ramu Errabelli, Vijaya L. Manthati, Adeniyi Michael Adebesin, Deb K. Barma, Deepan Barma, Victor Garcia, Fan Zhang, Michal Laniado Schwartzman, John R. Falck

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.

Original language	English (US)
Article number	126616
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	19
DOIs	https://doi.org/10.1016/j.bmcl.2019.08.020
State	Published - Oct 1 2019
Externally published	Yes

Keywords

Antagonist
Bioisosteric replacement
Eicosanoid
Hypertension
QDEGARKRKXEQDF-AAHZGTINSA-M
Vascular sensitization

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2019.08.020

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Dakarapu, R., Errabelli, R., Manthati, V. L., Michael Adebesin, A., Barma, D. K., Barma, D., Garcia, V., Zhang, F., Laniado Schwartzman, M., & Falck, J. R. (2019). 19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension. Bioorganic and Medicinal Chemistry Letters, 29(19), [126616]. https://doi.org/10.1016/j.bmcl.2019.08.020

Dakarapu, R, Errabelli, R, Manthati, VL, Michael Adebesin, A, Barma, DK, Barma, D, Garcia, V, Zhang, F, Laniado Schwartzman, M & Falck, JR 2019, '19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension', Bioorganic and Medicinal Chemistry Letters, vol. 29, no. 19, 126616. https://doi.org/10.1016/j.bmcl.2019.08.020

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title = "19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension",

abstract = "19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.",

keywords = "Antagonist, Bioisosteric replacement, Eicosanoid, Hypertension, QDEGARKRKXEQDF-AAHZGTINSA-M, Vascular sensitization",

author = "Rambabu Dakarapu and Ramu Errabelli and Manthati, {Vijaya L.} and {Michael Adebesin}, Adeniyi and Barma, {Deb K.} and Deepan Barma and Victor Garcia and Fan Zhang and {Laniado Schwartzman}, Michal and Falck, {John R.}",

note = "Funding Information: Financial support from the Robert A. Welch Foundation ( I-0011 ), the Dr. Ralph and Marian Falk Medical Research Trust Bank of America , N.A., Trustee, and NIH HL034300 and HL111392 . Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

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doi = "10.1016/j.bmcl.2019.08.020",

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AU - Dakarapu, Rambabu

AU - Errabelli, Ramu

AU - Manthati, Vijaya L.

AU - Michael Adebesin, Adeniyi

AU - Barma, Deb K.

AU - Barma, Deepan

AU - Garcia, Victor

AU - Zhang, Fan

AU - Laniado Schwartzman, Michal

AU - Falck, John R.

N1 - Funding Information: Financial support from the Robert A. Welch Foundation ( I-0011 ), the Dr. Ralph and Marian Falk Medical Research Trust Bank of America , N.A., Trustee, and NIH HL034300 and HL111392 . Publisher Copyright: © 2019 Elsevier Ltd

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.

AB - 19-Hydroxyeicosatetraenoic acid (19-HETE, 1), a metabolically and chemically labile cytochrome P450 eicosanoid, has diverse biological activities including antagonism of the vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE, 2). A SAR study was conducted to develop robust analogs of 1 with improved in vitro and in vivo efficacy. Analogs were screened in vitro for inhibition of 20-HETE-induced sensitization of rat renal preglomerular microvessels toward phenylephrine and demonstrated to normalize the blood pressure of male Cyp4a14(-/-) mice that display androgen-driven, 20-HETE-dependent hypertension.

KW - Antagonist

KW - Bioisosteric replacement

KW - Eicosanoid

KW - Hypertension

KW - QDEGARKRKXEQDF-AAHZGTINSA-M

KW - Vascular sensitization

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19-Hydroxyeicosatetraenoic acid analogs: Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension

Abstract

Keywords

ASJC Scopus subject areas

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