PMID- 30059891
OWN - NLM
STAT- MEDLINE
DCOM- 20190422
LR  - 20190422
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Linking)
VI  - 80
DP  - 2018 Oct
TI  - Discovery of polar spirocyclic orally bioavailable urea inhibitors of soluble 
      epoxide hydrolase.
PG  - 655-667
LID - S0045-2068(18)30465-6 [pii]
LID - 10.1016/j.bioorg.2018.07.014 [doi]
AB  - Spirocyclic 1-oxa-9-azaspiro[5.5]undecan-4-amine scaffold was explored as a basis 
      for the design of potential inhibitors of soluble epoxide hydrolase (sEH). 
      Synthesis and testing of the initial SAR-probing library followed by biochemical 
      testing against sEH allowed nominating a racemic lead compound (+/-)-22. The latter 
      showed remarkable (> 0.5 mM) solubility in aqueous phosphate buffer solution, 
      unusually low (for sEH inhibitors) lipophilicity as confirmed by experimentally 
      determined logD(7.4) of 0.99, and an excellent oral bioavailability in mice (as 
      well as other pharmacokinetic characteristics). Individual enantiomer profiling 
      revealed that the inhibitory potency primarily resided with the dextrorotatory 
      eutomer (+)-22 (IC(50) 4.99 +/- 0.18 nM). For the latter, a crystal structure of 
      its complex with a C-terminal domain of sEH was obtained and resolved. These data 
      fully validate (+)-22 as a new non-racemic advanced lead compound for further 
      development as a potential therapeutic agent for use in such areas as 
      cardiovascular disease, inflammation and pain.
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Lukin, Alexey
AU  - Lukin A
AD  - Lomonosov Institute of Fine Chemical Technologies, Moscow Technological 
      University, Moscow 117571, Russian Federation.
FAU - Kramer, Jan
AU  - Kramer J
AD  - Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, 
      Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Hartmann, Markus
AU  - Hartmann M
AD  - Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, 
      Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Weizel, Lilia
AU  - Weizel L
AD  - Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, 
      Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Hernandez-Olmos, Victor
AU  - Hernandez-Olmos V
AD  - Fraunhofer IME-TMP, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Falahati, Konstantin
AU  - Falahati K
AD  - Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Strasse 7, 60438 Frankfurt, Germany.
FAU - Burghardt, Irene
AU  - Burghardt I
AD  - Fraunhofer IME-TMP, Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Kalinchenkova, Natalia
AU  - Kalinchenkova N
AD  - Lomonosov Institute of Fine Chemical Technologies, Moscow Technological 
      University, Moscow 117571, Russian Federation.
FAU - Bagnyukova, Darya
AU  - Bagnyukova D
AD  - Lomonosov Institute of Fine Chemical Technologies, Moscow Technological 
      University, Moscow 117571, Russian Federation.
FAU - Zhurilo, Nikolay
AU  - Zhurilo N
AD  - Lomonosov Institute of Fine Chemical Technologies, Moscow Technological 
      University, Moscow 117571, Russian Federation.
FAU - Rautio, Jarkko
AU  - Rautio J
AD  - School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
FAU - Forsberg, Markus
AU  - Forsberg M
AD  - School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
FAU - Ihalainen, Jouni
AU  - Ihalainen J
AD  - School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
FAU - Auriola, Seppo
AU  - Auriola S
AD  - School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
FAU - Leppanen, Jukka
AU  - Leppanen J
AD  - School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.
FAU - Konstantinov, Igor
AU  - Konstantinov I
AD  - N. D. Zelinsky Institute of Organic Chemistry, 47 Leninsky Prospect, Moscow 
      119991, Russian Federation.
FAU - Pogoryelov, Denys
AU  - Pogoryelov D
AD  - Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 
      60438 Frankfurt, Germany.
FAU - Proschak, Ewgenij
AU  - Proschak E
AD  - Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, 
      Max-von-Laue-Strasse 9, 60438 Frankfurt, Germany.
FAU - Dar'in, Dmitry
AU  - Dar'in D
AD  - Saint Petersburg State University, Saint Petersburg 199034, Russian Federation.
FAU - Krasavin, Mikhail
AU  - Krasavin M
AD  - Saint Petersburg State University, Saint Petersburg 199034, Russian Federation. 
      Electronic address: m.krasavin@spbu.ru.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180717
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Spiro Compounds)
RN  - 8W8T17847W (Urea)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
SB  - IM
MH  - Enzyme Inhibitors/*chemistry/*pharmacology
MH  - Epoxide Hydrolases/*antagonists & inhibitors/metabolism
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Molecular Docking Simulation
MH  - Recombinant Proteins/metabolism
MH  - Solubility
MH  - Spiro Compounds/*chemistry/*pharmacology
MH  - Urea/*analogs & derivatives/*pharmacology
OTO - NOTNLM
OT  - 1-Oxa-9-azaspiro[5.5]undecan-4-amine
OT  - Distomer
OT  - Eutomer
OT  - Low LogD
OT  - Oral bioavailability
OT  - Orthogonal periphery group variation
OT  - Phosphate buffer solubility
OT  - Prins reaction
OT  - Protein-ligand crystal structure
OT  - Spirocyclic
EDAT- 2018/07/31 06:00
MHDA- 2019/04/23 06:00
CRDT- 2018/07/31 06:00
PHST- 2018/05/11 00:00 [received]
PHST- 2018/07/05 00:00 [revised]
PHST- 2018/07/12 00:00 [accepted]
PHST- 2018/07/31 06:00 [pubmed]
PHST- 2019/04/23 06:00 [medline]
PHST- 2018/07/31 06:00 [entrez]
AID - S0045-2068(18)30465-6 [pii]
AID - 10.1016/j.bioorg.2018.07.014 [doi]
PST - ppublish
SO  - Bioorg Chem. 2018 Oct;80:655-667. doi: 10.1016/j.bioorg.2018.07.014. Epub 2018 
      Jul 17.