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 | |
| State | Published - Oct 1 2019 |
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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
Cite this
19-Hydroxyeicosatetraenoic acid analogs : Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension. / Dakarapu, Rambabu; Errabelli, Ramu; Manthati, Vijaya L.; Michael Adebesin, Adeniyi; Barma, Deb K.; Barma, Deepan; Garcia, Victor; Zhang, Fan; Laniado Schwartzman, Michal; Falck, J R.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 19, 126616, 01.10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 19-Hydroxyeicosatetraenoic acid analogs
T2 - Antagonism of 20-hydroxyeicosatetraenoic acid-induced vascular sensitization and hypertension
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, J R
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
UR - http://www.scopus.com/inward/record.url?scp=85070704651&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070704651&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2019.08.020
DO - 10.1016/j.bmcl.2019.08.020
M3 - Article
VL - 29
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 19
M1 - 126616
ER -