PMID- 32891856
OWN - NLM
STAT- MEDLINE
DCOM- 20210302
LR  - 20211002
IS  - 1090-2120 (Electronic)
IS  - 0045-2068 (Print)
IS  - 0045-2068 (Linking)
VI  - 103
DP  - 2020 Oct
TI  - Development of multitarget inhibitors for the treatment of pain: Design, 
      synthesis, biological evaluation and molecular modeling studies.
PG  - 104165
LID - S0045-2068(20)31462-0 [pii]
LID - 10.1016/j.bioorg.2020.104165 [doi]
AB  - Multitarget-directed ligands are a promising class of drugs for discovering 
      innovative new therapies for difficult to treat diseases. In this study, we 
      designed dual inhibitors targeting the human fatty acid amide hydrolase (FAAH) 
      enzyme and human soluble epoxide hydrolase (sEH) enzyme. Targeting both of these 
      enzymes concurrently with single target inhibitors synergistically reduces 
      inflammatory and neuropathic pain; thus, dual FAAH/sEH inhibitors are likely to 
      be powerful analgesics. Here, we identified the piperidinyl-sulfonamide moiety as 
      a common pharmacophore and optimized several inhibitors to have excellent 
      inhibition profiles on both targeted enzymes simultaneously. In addition, several 
      inhibitors show good predicted pharmacokinetic properties. These results suggest 
      that this series of inhibitors has the potential to be further developed as new 
      lead candidates and therapeutics in pain management.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Wilt, Stephanie
AU  - Wilt S
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Kodani, Sean
AU  - Kodani S
AD  - Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, 
      University of California Davis, Davis, CA 95616, United States.
FAU - Le, Thanh N H
AU  - Le TNH
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Nguyen, Lato
AU  - Nguyen L
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Vo, Nghi
AU  - Vo N
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Ly, Tanya
AU  - Ly T
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Rodriguez, Mark
AU  - Rodriguez M
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Hudson, Paula K
AU  - Hudson PK
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States.
FAU - Morisseau, Christophe
AU  - Morisseau C
AD  - Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, 
      University of California Davis, Davis, CA 95616, United States.
FAU - Hammock, Bruce D
AU  - Hammock BD
AD  - Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, 
      University of California Davis, Davis, CA 95616, United States.
FAU - Pecic, Stevan
AU  - Pecic S
AD  - Department of Chemistry and Biochemistry, California State University Fullerton, 
      Fullerton, CA 92831, United States. Electronic address: specic@fullerton.edu.
LA  - eng
GR  - P42 ES004699/ES/NIEHS NIH HHS/United States
GR  - R35 ES030443/ES/NIEHS NIH HHS/United States
GR  - SC2 GM135020/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200828
PL  - United States
TA  - Bioorg Chem
JT  - Bioorganic chemistry
JID - 1303703
SB  - IM
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Docking Simulation/*methods
MH  - Pain/*drug therapy
MH  - Structure-Activity Relationship
PMC - PMC7723751
MID - NIHMS1648000
OTO - NOTNLM
OT  - ADMET predictions
OT  - Designed multiple ligands
OT  - Docking experiments
OT  - Enzyme inhibition
OT  - Molecular modeling
OT  - Structure-Activity Relationship (SAR) study
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2020/09/07 06:00
MHDA- 2021/03/03 06:00
PMCR- 2021/10/01
CRDT- 2020/09/06 20:25
PHST- 2020/07/09 00:00 [received]
PHST- 2020/08/05 00:00 [revised]
PHST- 2020/08/12 00:00 [accepted]
PHST- 2020/09/07 06:00 [pubmed]
PHST- 2021/03/03 06:00 [medline]
PHST- 2020/09/06 20:25 [entrez]
PHST- 2021/10/01 00:00 [pmc-release]
AID - S0045-2068(20)31462-0 [pii]
AID - 10.1016/j.bioorg.2020.104165 [doi]
PST - ppublish
SO  - Bioorg Chem. 2020 Oct;103:104165. doi: 10.1016/j.bioorg.2020.104165. Epub 2020 
      Aug 28.