Synthesis, In Vitro Profiling, and In Vivo Evaluation of Benzohomoadamantane-Based Ureas for Visceral Pain: A New Indication for Soluble Epoxide Hydrolase Inhibitors

被引：6

作者：

Codony, Sandra ^{[1
,2
]}

Entrena, Jose M. ^{[3
]}

Calvo-Tusell, Carla ^{[4
,5
]}

Jora, Beatrice ^{[1
,2
]}

Gonzalez-Cano, Rafael ^{[6
,7
]}

Osuna, Silvia ^{[4
,5
,8
]}

Corpas, Ruben ^{[9
,10
]}

Morisseau, Christophe ^{[11
,12
]}

Perez, Belen ^{[13
]}

Barniol-Xicota, Marta ^{[14
]}

Grinan-Ferre, Christian ^{[15
]}

Perez, Concepcion ^{[16
]}

Isabel Rodriguez-Franco, Maria ^{[16
]}

Martinez, Anton L. ^{[17
]}

Isabel Loza, M. ^{[17
]}

Pallas, Merce ^{[15
]}

Verhelst, Steven H. L. ^{[14
,18
]}

Sanfeliu, Coral ^{[9
,10
]}

Feixas, Ferran ^{[4
,5
]}

Hammock, Bruce D. ^{[11
,12
]}

Brea, Jose ^{[17
]}

Cobos, Enrique J. ^{[6
,7
]}

Vazquez, Santiago ^{[1
,2
]}

机构：

[1] Univ Barcelona, Lab Quim Farmaceut, Unitat Associada, Fac Farm & Ciencies Alimentacio,CSIC, Barcelona 08028, Spain

[2] Univ Barcelona, Inst Biomed IBUB, Barcelona 08028, Spain

[3] Univ Granada, Sci Instrumentat Ctr, Anim Behav Res Unit, Parque Tecnol Ciencias Salud, Granada 18100, Spain

[4] Univ Girona, CompBioLab Grp, Dept Quim, Girona 17003, Spain

[5] Univ Girona, Inst Quim Computac & Catalisi IQCC, Girona 17003, Spain

[6] Univ Granada, Dept Pharmacol, Fac Med, Granada 18016, Spain

[7] Univ Granada, Biomed Res Ctr, Neurosci Inst, Biosanit Res Inst Ibs GRANADA, Granada 18016, Spain

[8] Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain

[9] CSIC, Inst Biomed Res Barcelona IIBB, Barcelona 08036, Spain

[10] IDIBAPS, Barcelona 08036, Spain

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

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

[13] Autonomous Univ Barcelona, Inst Neurosci, Dept Pharmacol Therapeut & Toxicol, Barcelona 08193, Spain

[14] Univ Leuven, KU Leuven, Dept Cellular & Mol Med, Lab Chem Biol, B-3000 Leuven, Belgium

[15] Univ Barcelona NeuroUB, Fac Pharm & Food Sci, Inst Neurosci, Pharmacol Sect,Dept Pharmacol Toxicol & Therapeut, Barcelona 08028, Spain

[16] CSIC, Inst Med Chem, Madrid 28006, Spain

[17] Univ Santiago de Compostela USC, CIMUS Res Ctr, Biofarma Res Grp, Drug Screening Platform, Santiago De Compostela 15782, Spain

[18] AG Chem Prote, Leibniz Inst Analyt Sci ISAS, D-44227 Dortmund, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 20期

基金：

欧洲研究理事会;

关键词：

ARACHIDONIC-ACID METABOLISM; NMDA RECEPTOR ANTAGONIST; MOLECULAR-DYNAMICS; EPOXYEICOSATRIENOIC ACIDS; BIOLOGICAL EVALUATION; ATOMIC CHARGES; PHARMACOKINETICS; SORAFENIB; SYSTEM; SINGLE;

D O I：

10.1021/acs.jmedchem.2c00515

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The soluble epoxide hydrolase (sEH) has been suggested as a pharmacological target for the treatment of several diseases, including pain-related disorders. Herein, we report further medicinal chemistry around new benzohomoadamantane-based sEH inhibitors (sEHI) in order to improve the drug metabolism and pharmacokinetics properties of a previous hit. After an extensive in vitro screening cascade, molecular modeling, and in vivo pharmacokinetics studies, two candidates were evaluated in vivo in a murine model of capsaicin-induced allodynia. The two compounds showed an anti-allodynic effect in a dose-dependent manner. Moreover, the most potent compound presented robust analgesic efficacy in the cyclophosphamide-induced murine model of cystitis, a well-established model of visceral pain. Overall, these results suggest painful bladder syndrome as a new possible indication for sEHI, opening a new range of applications for them in the visceral pain field.

引用

页码：13660 / 13680

页数：21

共 50 条

[1] Soluble Epoxide Hydrolase Inhibitors: Design, Synthesis, in vitro Profiling and in vivo Evaluation in Murine Models of Pain
Vazquez, Santiago
Codony, Sandra
Entrena, Jose M.
Jora, Beatrice
Gonzalez-Cano, Rafael
Loza, M. I.
Brea, Jose
Morisseau, Christophe
Bartra, Clara
Sanfeliu, Coral
FASEB JOURNAL, 2022, 36
[2] From the Design to the In Vivo Evaluation of Benzohomoadamantane-Derived Soluble Epoxide Hydrolase Inhibitors for the Treatment of Acute Pancreatitis
Codony, Sandra
Calvo-Tusell, Carla
Valverde, Elena
Osuna, Silvia
Morisseau, Christophe
Isabel Loza, M.
Brea, Jose
Perez, Concepcion
Isabel Rodriguez-Franco, Maria
Pizarro-Delgado, Javier
Corpas, Ruben
Grinan-Ferre, Christian
Pallas, Merce
Sanfeliu, Coral
Vazquez-Carrera, Manuel
Hammock, Bruce D.
Feixas, Ferran
Vazquez, Santiago
JOURNAL OF MEDICINAL CHEMISTRY, 2021, 64 (09) : 5429 - 5446
[3] Novel Soluble Epoxide Hydrolase Inhibitors Featuring a 2-Oxaadamantane Moiety: Synthesis, in vitro Profiling and in vivo Evaluation in Murine Models of Acute Pancreatitis
Vazquez, Santiago
Codony, Sandra
Pizarro, Javier
Pujol, Eugenia
Valverde, Elena
Loza, Isabel
Brea, Jose M.
Saez, Elena
Oyarzabal, Julen
Vazquez-Carrera, Manuel
Leiva, Rosana
FASEB JOURNAL, 2018, 32 (01):
[4] 2-Oxaadamant-1-yl Ureas as Soluble Epoxide Hydrolase Inhibitors: In Vivo Evaluation in a Murine Model of Acute Pancreatitis
Codony, Sandra
Pujol, Eugenia
Pizarro, Javier
Feixas, Ferran
Valverde, Elena
Isabel Loza, M.
Brea, Jose M.
Saez, Elena
Oyarzabal, Julen
Pineda-Lucena, Antonio
Perez, Belen
Perez, Concepcion
Isabel Rodriguez-Franco, Maria
Leiva, Rosana
Osuna, Silvia
Morisseau, Christophe
Hammock, Bruce D.
Vaquez-Carrera, Manuel
Vazquez, Santiago
JOURNAL OF MEDICINAL CHEMISTRY, 2020, 63 (17) : 9237 - 9257
[5] Synthesis and evaluation of conformationally restricted soluble epoxide hydrolase (sEH) inhibitors
Hwang, Sung Hee
Tsai, Hsing-Ju
Morisseau, Christophe
Do, Zung
Hammock, Bruce D.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 835 - 835
[6] Synthesis of Bicyclic Isocyanates and Bioisosteric 1,3-Disubstituted Ureas as Soluble Epoxide Hydrolase Inhibitors
V. V. Burmistrov
V. S. D’yachenko
E. V. Rasskazova
G. M. Butov
Russian Journal of Organic Chemistry, 2019, 55 : 1166 - 1176
[7] Synthesis of Bicyclic Isocyanates and Bioisosteric 1,3-Disubstituted Ureas as Soluble Epoxide Hydrolase Inhibitors
Burmistrov, V. V.
D'yachenko, V. S.
Rasskazova, E., V
Butov, G. M.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY, 2019, 55 (08) : 1166 - 1176
[8] Design, synthesis and evaluation of non-urea inhibitors of soluble epoxide hydrolase
Pecic, Stevan
Deng, Shi-Xian
Morisseau, Christophe
Hammock, Bruce D.
Landry, Donald W.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2012, 22 (01) : 601 - 605
[9] In vitro and in vivo metabolism of N-adamantyl substituted urea-based soluble epoxide hydrolase inhibitors
Liu, Jun-Yan
Tsai, Hsing-Ju
Morisseau, Christophe
Lango, Jozsef
Hwang, Sung Hee
Watanabe, Takaho
Kim, In-Hae
Hammock, Bruce D.
BIOCHEMICAL PHARMACOLOGY, 2015, 98 (04) : 718 - 731
[10] Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy
Lee, Kin Sing Stephen
Liu, Jun-Yan
Wagner, Karen M.
Pakhomova, Svetlana
Dong, Hua
Morisseau, Christophe
Fu, Samuel H.
Yang, Jun
Wang, Peng
Ulu, Arzu
Mate, Christina A.
Nguyen, Long V.
Hwang, Sung Hee
Edin, Matthew L.
Mara, Alexandria A.
Wulff, Heike
Newcomer, Marcia E.
Zeldin, Darryl C.
Hammock, Bruce D.
JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (16) : 7016 - 7030

← 1 2 3 4 5 →