PMID- 31670489
OWN - NLM
STAT- MEDLINE
DCOM- 20210128
LR  - 20240329
IS  - 1860-7187 (Electronic)
IS  - 1860-7179 (Print)
IS  - 1860-7179 (Linking)
VI  - 15
IP  - 1
DP  - 2020 Jan 7
TI  - Dual Farnesoid X Receptor/Soluble Epoxide Hydrolase Modulators Derived from 
      Zafirlukast.
PG  - 50-67
LID - 10.1002/cmdc.201900576 [doi]
AB  - The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase 
      (sEH) are validated molecular targets to treat metabolic disorders such as 
      non-alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has 
      demonstrated a triad of anti-NASH effects and thus may generate synergistic 
      efficacy. Here we report dual FXR activators/sEH inhibitors derived from the 
      anti-asthma drug Zafirlukast. Systematic structural optimization of the scaffold 
      has produced favorable dual potency on FXR and sEH while depleting the original 
      cysteinyl leukotriene receptor antagonism of the lead drug. The resulting 
      polypharmacological activity profile holds promise in the treatment of 
      liver-related metabolic diseases.
CI  - (c) 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
FAU - Schierle, Simone
AU  - Schierle S
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Helmstadter, Moritz
AU  - Helmstadter M
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Schmidt, Jurema
AU  - Schmidt J
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Hartmann, Markus
AU  - Hartmann M
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Horz, Maximiliane
AU  - Horz M
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Kaiser, Astrid
AU  - Kaiser A
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Weizel, Lilia
AU  - Weizel L
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Heitel, Pascal
AU  - Heitel P
AUID- ORCID: 0000-0001-5187-6342
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Proschak, Anna
AU  - Proschak A
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Hernandez-Olmos, Victor
AU  - Hernandez-Olmos V
AD  - Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch for 
      Translational Medicine and Pharmacology TMP, Theodor-Stern-Kai 7, 60596, 
      Frankfurt am Main, Germany.
FAU - Proschak, Ewgenij
AU  - Proschak E
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
FAU - Merk, Daniel
AU  - Merk D
AUID- ORCID: 0000-0002-5359-8128
AD  - Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, 
      Max-von-Laue-Str. 9, 60438, Frankfurt, Germany.
LA  - eng
GR  - P41 GM103311/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20191119
PL  - Germany
TA  - ChemMedChem
JT  - ChemMedChem
JID - 101259013
RN  - 0 (Indoles)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Phenylcarbamates)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Sulfonamides)
RN  - 0 (Tosyl Compounds)
RN  - 0C5V0MRU6P (farnesoid X-activated receptor)
RN  - EC 1.14.14.23 (Cholesterol 7-alpha-Hydroxylase)
RN  - EC 3.3.2.- (Epoxide Hydrolases)
RN  - XZ629S5L50 (zafirlukast)
SB  - IM
MH  - Binding Sites
MH  - Catalytic Domain
MH  - Cholesterol 7-alpha-Hydroxylase/genetics/metabolism
MH  - Drug Evaluation, Preclinical
MH  - Epoxide Hydrolases/*antagonists & inhibitors/genetics/metabolism
MH  - Gene Expression Regulation/drug effects
MH  - Hep G2 Cells
MH  - Humans
MH  - Indoles
MH  - Membrane Transport Proteins/genetics/metabolism
MH  - Molecular Docking Simulation
MH  - Non-alcoholic Fatty Liver Disease/metabolism/pathology
MH  - Phenylcarbamates
MH  - Receptors, Cytoplasmic and Nuclear/*agonists/genetics/metabolism
MH  - Structure-Activity Relationship
MH  - Sulfonamides
MH  - Tosyl Compounds/*chemistry/metabolism/pharmacology
PMC - PMC7004070
OTO - NOTNLM
OT  - NAFLD
OT  - NASH
OT  - Polypharmacology
OT  - non-alcoholic steatohepatitis
OT  - nuclear receptor
EDAT- 2019/11/02 06:00
MHDA- 2021/01/29 06:00
PMCR- 2020/02/06
CRDT- 2019/11/01 06:00
PHST- 2019/10/15 00:00 [received]
PHST- 2019/10/21 00:00 [revised]
PHST- 2019/11/02 06:00 [pubmed]
PHST- 2021/01/29 06:00 [medline]
PHST- 2019/11/01 06:00 [entrez]
PHST- 2020/02/06 00:00 [pmc-release]
AID - CMDC201900576 [pii]
AID - 10.1002/cmdc.201900576 [doi]
PST - ppublish
SO  - ChemMedChem. 2020 Jan 7;15(1):50-67. doi: 10.1002/cmdc.201900576. Epub 2019 Nov 
      19.