Discovery of the First in Vivo Active Inhibitors of the Soluble Epoxide Hydrolase Phosphatase Domain

被引：22

作者：

Kramer, Jan S. ^{[1
]}

Woltersdorf, Stefano ^{[1
]}

Duflot, Thomas ^{[2
,7
]}

Hiesinger, Kerstin ^{[1
]}

Lillich, Felix F. ^{[1
]}

Knoell, Felix ^{[1
]}

Wittmann, Sandra K. ^{[1
]}

Klingler, Franca-M. ^{[1
]}

Brunst, Steffen ^{[1
]}

Chaikuad, Apirat ^{[1
,3
]}

Morisseau, Christophe ^{[4
,5
]}

Hammock, Bruce D. ^{[4
,5
]}

Buccellati, Carola ^{[6
,11
]}

Sala, Angelo ^{[6
,11
]}

Rovati, G. Enrico ^{[6
,11
]}

Leuillier, Matthieu ^{[7
]}

Fraineau, Sylvain ^{[7
]}

Rondeaux, Julie ^{[7
]}

Hernandez-Olmos, Victor ^{[1
,8
]}

Heering, Jan ^{[1
,8
]}

Merk, Daniel ^{[1
]}

Pogoryelov, Denys ^{[9
]}

Steinhilber, Dieter ^{[1
]}

Knapp, Stefan ^{[1
,2
]}

Bellien, Jeremy ^{[7
,10
]}

Proschak, Ewgenij ^{[1
]}

机构：

[1] Goethe Univ Frankfurt, Inst Pharmaceut Chem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[2] Rouen Univ Hosp, Lab Pharmacokinet Toxicol & Pharmacogenet, F-76000 Rouen, France

[3] Goethe Univ Frankfurt, Buchmann Inst Life Sci, Struct Genom Consortium, Max von Laue Str 15, D-60438 Frankfurt, Germany

[4] Univ Calif Davis, Dept Entomol & Nematol, Davis, CA 95616 USA

[5] Univ Calif Davis, UC Davis Comprehens Canc Ctr, Davis, CA 95616 USA

[6] Univ Milan, Dept Pharmacol & Biomol Sci, Via Balzaretti 9, I-20133 Milan, Italy

[7] Normandie Univ, UNIROUEN, INSERM, U1096, 1 Rue Germont, F-76000 Rouen, France

[8] Fraunhofer Inst Mol Biol & Appl Ecol IME, Branch Translat Med & Pharmacol TMP, Theodor Stern Kai 7, D-60596 Frankfurt, Germany

[9] Goethe Univ Frankfurt, Inst Biochem, Max von Laue Str 9, D-60438 Frankfurt, Germany

[10] Rouen Univ Hosp, Dept Clin Pharmacol, F-76000 Rouen, France

[11] Univ Milan, Dept Pharmaceut Sci, Via Colombo 60, Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 18期

基金：

英国惠康基金; 加拿大创新基金会; 巴西圣保罗研究基金会;

关键词：

ACIDS; MODULATION; TARGET; AGENTS;

D O I：

10.1021/acs.jmedchem.9b00445

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The emerging pharmacological target soluble epoxide hydrolase (sEH) is a bifunctional enzyme exhibiting two different catalytic activities that are located in two distinct domains. Although the physiological role of the C-terminal hydrolase domain is well-investigated, little is known about its phosphatase activity, located in the N-terminal phosphatase domain of sEH (sEH-P). Herein we report the discovery and optimization of the first inhibitor of human and rat sEH-P that is applicable in vivo. X-ray structure analysis of the sEH phosphatase domain complexed with an inhibitor provides insights in the molecular basis of small-molecule sEH-P inhibition and helps to rationalize the structure-activity relationships. 4-(4-(3,4-Dichlorophenyl)-5-phenyloxazol-2-yl)butanoic acid (22b, SWE101) has an excellent pharmacokinetic and pharmacodynamic profile in rats and enables the investigation of the physiological and pathophysiological role of sEH-P in vivo.

引用

页码：8443 / 8460

页数：18

共 50 条

[21] Application of Encoded Library Technology (ELT) to the discovery of soluble epoxide hydrolase inhibitors
Evindar, Ghotas
Acharya, Raksha A.
Arico-Muendel, Christopher
Belyanskaya, Svetlana
Brown, Joi
Clark, Matthew A.
Centrella, Paolo A.
Cuozzo, John W.
Davie, Christopher P.
Ding, Yun
Franklin, Joe J.
Gross, Jeffrey W.
Israel, David I.
Jolivette, Larry J.
Jurewicz, Anthony J.
Lakdawala, Ami S.
Li, Fan
Li, Hu
Lind, Kenneth E.
Marino, Joseph P.
Morgan, Barry
Messer, Jeff A.
Roethke, Theresa J.
Sargent, Katie I.
Shewchuk, Lisa M.
Skinner, Steven R.
Svendsen, Jennifer L.
Xie, Wensheng
Yang, Hongfang
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238
[22] Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble epoxide hydrolase
Lukin, Alexey
Kramer, Jan
Hartmann, Markus
Weizel, Lilia
Hernandez-Olmos, Victor
Falahati, Konstantin
Burghardt, Irene
Kalinchenkova, Natalia
Bagnyukova, Darya
Zhurilo, Nikolay
Rautio, Jarkko
Forsberg, Markus
Ihalainen, Jouni
Auriola, Seppo
Leppanen, Jukka
Konstantinov, Igor
Pogoryelov, Denys
Proschak, Ewgenij
Dar'in, Dmitry
Krasavin, Mikhail
BIOORGANIC CHEMISTRY, 2018, 80 : 655 - 667
[23] Prospects for the inhibition of the phosphatase domain of human soluble epoxide hydrolase (sEH-P)
Burmistrov, V. V.
Karlov, D. S.
Butov, G. M.
Novakov, I. A.
RUSSIAN CHEMICAL BULLETIN, 2021, 70 (06) : 1067 - 1074
[24] An insect farnesyl phosphatase homologous to the N-terminal domain of soluble epoxide hydrolase
Cao, Li
Zhang, Ping
Grant, David F.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2009, 380 (01) : 188 - 192
[25] Prospects for the inhibition of the phosphatase domain of human soluble epoxide hydrolase (sEH-P)
V. V. Burmistrov
D. S. Karlov
G. M. Butov
I. A. Novakov
Russian Chemical Bulletin, 2021, 70 : 1067 - 1074
[26] Structure/function analysis:: Active site mutants of the N-terminal phosphatase domain of human soluble epoxide hydrolase
Cronin, A
Homburg, S
Dürk, H
Oesch, F
Arand, M
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2003, 367 : R126 - R126
[27] Natural soluble epoxide hydrolase inhibitors from Alisma orientale and their potential mechanism with soluble epoxide hydrolase
Zhao, Wen-Yu
Zhang, Xin-Yue
Zhou, Mei-Rong
Tian, Xiang-Ge
Lv, Xia
Zhang, Hou-Li
Deng, Sa
Zhang, Bao-Jing
Sun, Cheng-Peng
Ma, Xiao-Chi
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, 2021, 183 : 811 - 817
[28] Adamantyl thioureas as soluble epoxide hydrolase inhibitors
Burmistrov, Vladimir
Morisseau, Christophe
Pitushkin, Dmitry
Karlov, Dmitry
Fayzullin, Robert R.
Butov, Gennady M.
Hammock, Bruce D.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (13) : 2302 - 2313
[29] Soluble epoxide hydrolase inhibitors: a patent review
Shen, Hong C.
EXPERT OPINION ON THERAPEUTIC PATENTS, 2010, 20 (07) : 941 - 956
[30] Soluble Epoxide Hydrolase Inhibitors and Cardiovascular Diseases
Wang, Zhen-He
Davis, Benjamin B.
Jiang, De-Qian
Zhao, Ting-Ting
Xu, Dan-Yan
CURRENT VASCULAR PHARMACOLOGY, 2013, 11 (01) : 105 - 111

← 1 2 3 4 5 →