Potent and Selective Inhibitors of Human Reticulocyte 12/15-Lipoxygenase as Anti-Stroke Therapies

被引：83

作者：

Rai, Ganesha ^{[2
]}

Joshi, Netra ^{[3
]}

Jung, Joo Eun ^{[1
]}

Liu, Yu ^{[1
]}

Schultz, Lena ^{[2
]}

Yasgar, Adam ^{[2
]}

Perry, Steve ^{[3
]}

Diaz, Giovanni ^{[3
]}

Zhang, Qiangli ^{[3
]}

Kenyon, Victor ^{[3
]}

Jadhav, Ajit ^{[2
]}

Simeonov, Anton ^{[2
]}

Lo, Eng H. ^{[1
]}

van Leyen, Klaus ^{[1
]}

Maloney, David J. ^{[2
]}

Holman, Theodore R. ^{[3
]}

机构：

[1] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Neuroprotect Res Lab,Dept Radiol, Charlestown, MA 02129 USA

[2] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA

[3] Univ Calif Santa Cruz, Dept Chem & Biochem, Santa Cruz, CA 95064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 10期

基金：

美国国家卫生研究院;

关键词：

SPONGE-DERIVED TERPENOIDS; 5-LIPOXYGENASE INHIBITION; HUMAN; 15-LIPOXYGENASE; 12/15; LIPOXYGENASE; OXIDATIVE STRESS; ARTERIAL-WALL; 12-LIPOXYGENASE; DISCOVERY; APOPTOSIS; ZILEUTON;

D O I：

10.1021/jm401915r

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A key challenge facing drug discovery today is variability of the drug target between species, such as with 12/15-lipoxygenase (12/15-LOX), which contributes to ischemic brain injury, but its human and rodent isozymes have different inhibitor specificities. In the current work, we have utilized a quantitative high-throughput (qHTS) screen to identify compound 1 (ML351), a novel chemotype for 12/15-LOX inhibition that has nanomolar potency (IC50 = 200 nM) against human 12/15-LOX and is protective against oxidative glutamate toxicity in mouse neuronal HT22 cells. In addition, it exhibited greater than 250-fold selectivity versus related LOX isozymes, was a mixed inhibitor, and did not reduce the active-site ferric ion. Lastly, 1 significantly reduced infarct size following permanent focal ischemia in a mouse model of ischemic stroke. As such, this represents the first report of a selective inhibitor of human 12/15-LOX with demonstrated in vivo activity in proof-of-concept mouse models of stroke.

引用

页码：4035 / 4048

页数：14

共 41 条

[31] Synthesis and SAR study of 4,5-diaryl-1H-imidazole-2(3H)-thione derivatives, as potent 15-lipoxygenase inhibitors
Assadieskandar, Amir
Amini, Mohsen
Salehi, Marjan
Sadeghian, Hamid
Alimardani, Maliheh
Sakhteman, Amirhossein
Nadri, Hamid
Shafiee, Abbas
BIOORGANIC & MEDICINAL CHEMISTRY, 2012, 20 (24) : 7160 - 7166
[32] Design, synthesis, molecular modelling and biological evaluation of novel 3-(2-naphthyl)-1-phenyl-1H-pyrazole derivatives as potent antioxidants and 15-Lipoxygenase inhibitors
Ali, Sahar A.
Awad, Samir Mohamed
Said, Ahmed Mohammed
Mahgoub, Shahenda
Taha, Heba
Ahmed, Naglaa Mohamed
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY, 2020, 35 (01) : 847 - 863
[33] Structure-activity relationship studies of flavonoids as potent inhibitors of human platelet 12-hLO, reticulocyte 15-hLO-1, and prostate epithelial 15-hLO-2
Vasquez-Martinez, Yesseny
Ohri, Rachana V.
Kenyon, Victor
Holman, Theodore R.
Sepulveda-Boza, Silvia
BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (23) : 7408 - 7425
[34] 5S,15S-Dihydroperoxyeicosatetraenoic Acid (5,15-diHpETE) as a Lipoxin Intermediate: Reactivity and Kinetics with Human Leukocyte 5-Lipoxygenase, Platelet 12-Lipoxygenase, and Reticulocyte 15-Lipoxygenase-1
Green, Abigail R.
Freedman, Cody
Tena, Jennyfer
Tourdot, Benjamin E.
Liu, Benjamin
Holinstat, Michael
Holman, Theodore R.
BIOCHEMISTRY, 2018, 57 (48) : 6726 - 6734
[35] CONVERSION OF HUMAN 15-LIPOXYGENASE TO AN EFFICIENT 12-LIPOXYGENASE - THE SIDE-CHAIN GEOMETRY OF AMINO-ACID-417 AND AMINO-ACID418 DETERMINE POSITIONAL SPECIFICITY
SLOANE, DL
LEUNG, R
BARNETT, J
CRAIK, CS
SIGAL, E
PROTEIN ENGINEERING, 1995, 8 (03): : 275 - 282
[36] 4-Chlorophenyl-N-furfuryl-1,2,4-triazole Methylacetamides as Significant 15-Lipoxygenase Inhibitors: an Efficient Approach for Finding Lead Anti-inflammatory Compounds
Yasin, Muhammad
Shahid, Wardah
Ashraf, Muhammad
Saleem, Muhammad
Muzaffar, Saima
Aziz-ur-Rehman
Ejaz, Syed Abid
Saeed, Amna
Majer, Thomas
Bhattarai, Keshab
Riaz, Naheed
ACS OMEGA, 2022, 7 (23): : 19721 - 19734
[37] Discovery of platelet-type 12-human lipoxygenase selective inhibitors by high-throughput screening of structurally diverse libraries
Deschamps, Joshua D.
Gautschi, Jeffrey T.
Whitman, Stephanie
Johnson, Tyler A.
Gassner, Nadine C.
Crews, Phillip
Holman, Theodore R.
BIOORGANIC & MEDICINAL CHEMISTRY, 2007, 15 (22) : 6900 - 6908
[38] Molecular Basis for the Reduced Catalytic Activity of the Naturally Occurring T560M Mutant of Human 12/15-Lipoxygenase That Has Been Implicated in Coronary Artery Disease
Schurmann, Kathrin
Anton, Monika
Ivanov, Igor
Richter, Constanze
Kuhn, Hartmut
Walther, Matthias
JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (27) : 23920 - 23927
[39] Design, synthesis, biological evaluation and docking studies of new 3-(4,5-dihydro-1H-pyrazol/isoxazol-5-yl)-2-phenyl-1H-indole derivatives as potent antioxidants and 15-lipoxygenase inhibitors
ElBordiny, Haydi Saher
El-Miligy, Mostafa Mahmoud
Kassab, Shaymaa Emam
Daabees, Hoda
El-Hawash, Soad Abdelhamid Mohamed
Ali, Waleed Ali Mohamed
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 145 : 594 - 605
[40] Discovery two potent and new inhibitors of 15-lipoxygenase: (E)-3-((3,4-dihydroxybenzylidene) amino)-7-hydroxy-2H-chromen-2-one and (E)-O-(4-(((7-hydroxy-2-oxo-2H-chromen-3-yl) imino)methine)phenyl)dimethylcarbamothioate
Nunez, Carolina
Morales, Nicole
Garcia-Beltran, Olimpo
Mascayano, Carolina
Fierro, Angelica
MEDICINAL CHEMISTRY RESEARCH, 2017, 26 (11) : 2707 - 2717

← 1 2 3 4 5 →