Pecic S

References (10)

Title : Structure-activity relationship studies of benzothiazole-phenyl analogs as multi-target ligands to alleviate pain without affecting normal behavior - Angelia_2022_Prostaglandins.Other.Lipid.Mediat__106702
Author(s) : Angelia J , Weng X , Solomatov A , Chin C , Fernandez A , Hudson PK , Morisseau C , Hammock BD , Kandasamy R , Pecic S
Ref : Prostaglandins Other Lipid Mediat , :106702 , 2022
Abstract : Soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH) are potential targets for several diseases. Previous studies have reported that concomitant selective inhibition of sEH and FAAH produced antinociception effects in an animal model of pain. However, the co-administration of a selective sEH inhibitor and a selective FAAH inhibitor might produce serious side effects due to drug-drug interactions that could complicate drug development in the long term. Thus, discovering dual sEH/FAAH inhibitors, single small molecules that can simultaneously inhibit both sEH and FAAH, would be a significant accomplishment in the medicinal chemistry field. Herein, we report the synthesis and biological evaluation of benzothiazole-phenyl-based analogs as potential dual sEH/FAAH inhibitors. This work represents a follow-up structure-activity relationship (SAR) and metabolic-stability studies of our best dual sEH/FAAH inhibitor identified previously, as well as in vivo evaluation of its effects on voluntary locomotor behavior in rats. Our SAR study indicates that trifluoromethyl groups on the aromatic rings are well tolerated by the targeted enzymes when placed at the ortho and para positions; however, they, surprisingly, did not improve metabolic stability in liver microsomes. Our behavioral studies indicate that doses of dual sEH/FAAH inhibitors that alleviate pain do not depress voluntary behavior in naive rats, which is a common side effect of currently available analgesic drugs (e.g., opioids). Thus, dual sEH/FAAH inhibitors may be a safe and effective approach to treat pain.
ESTHER : Angelia_2022_Prostaglandins.Other.Lipid.Mediat__106702
PubMedSearch : Angelia_2022_Prostaglandins.Other.Lipid.Mediat__106702
PubMedID: 36529320

Title : Synthesis, kinetic evaluation and molecular docking studies of donepezil-based acetylcholinesterase inhibitors - Makarian_2022_J.Mol.Struct_1247_
Author(s) : Makarian M , Gonzalez M , Salvador SM , Lorzadeh S , Hudson PK , Pecic S
Ref : J Mol Struct , 1247 : , 2022
Abstract : In an effort to develop new therapeutic agents to treat Alzheimer's disease, a series of donepezil-based analogs were designed, synthesized using an environmentally friendly route, and biologically evaluated for their inhibitory activity against electric eel acetylcholinesterase (AChE) enzyme. In vitro studies revealed that the phenyl moiety of donepezil can be successfully replaced with a pyridine ring leading to equally potent inhibitors of electric eel AChE. Further kinetic evaluations of the most potent inhibitor showed a dual-binding (mixed inhibition) mode, similar to donepezil. Molecular modeling studies suggest that several additional residues could be involved in the binding of this inhibitor in the human AChE enzyme active site compared to donepezil.
ESTHER : Makarian_2022_J.Mol.Struct_1247_
PubMedSearch : Makarian_2022_J.Mol.Struct_1247_
PubMedID: 35221376

Title : Further exploration of the structure-activity relationship of dual soluble epoxide hydrolase\/fatty acid amide hydrolase inhibitors - Wilt_2021_Bioorg.Med.Chem_51_116507
Author(s) : Wilt S , Kodani S , Valencia L , Hudson PK , Sanchez S , Quintana T , Morisseau C , Hammock BD , Kandasamy R , Pecic S
Ref : Bioorganic & Medicinal Chemistry , 51 :116507 , 2021
Abstract : Fatty acid amide hydrolase (FAAH) is a membrane protein that hydrolyzes endocannabinoids, and its inhibition produces analgesic and anti-inflammatory effects. The soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids. EETs have anti-inflammatory and inflammation resolving properties, thus inhibition of sEH consequently reduces inflammation. Concurrent inhibition of both enzymes may represent a novel approach in the treatment of chronic pain. Drugs with multiple targets can provide a superior therapeutic effect and a decrease in side effects compared to ligands with single targets. Previously, microwave-assisted methodologies were employed to synthesize libraries of benzothiazole analogs from which high affinity dual inhibitors (e.g. 3, sEH IC(50) = 9.6 nM; FAAH IC(50) = 7 nM) were identified. Here, our structure-activity relationship studies revealed that the 4-phenylthiazole moiety is well tolerated by both enzymes, producing excellent inhibition potencies in the low nanomolar range (e.g. 6o, sEH IC(50) = 2.5 nM; FAAH IC(50) = 9.8 nM). Docking experiments show that the new class of dual inhibitors bind within the catalytic sites of both enzymes. Prediction of several pharmacokinetic/pharmacodynamic properties suggest that these new dual inhibitors are good candidates for further in vivo evaluation. Finally, dual inhibitor 3 was tested in the Formalin Test, a rat model of acute inflammatory pain. The data indicate that 3 produces antinociception against the inflammatory phase of the Formalin Test in vivo and is metabolically stable following intraperitoneal administration in male rats. Further, antinociception produced by 3 is comparable to that of ketoprofen, a traditional nonsteroidal anti-inflammatory drug. The results presented here will help toward the long-term goal of developing novel non-opioid therapeutics for pain management.
ESTHER : Wilt_2021_Bioorg.Med.Chem_51_116507
PubMedSearch : Wilt_2021_Bioorg.Med.Chem_51_116507
PubMedID: 34794001

Title : Development of multitarget inhibitors for the treatment of pain: Design, synthesis, biological evaluation and molecular modeling studies - Wilt_2020_Bioorg.Chem_103_104165
Author(s) : Wilt S , Kodani S , Le TNH , Nguyen L , Vo N , Ly T , Rodriguez M , Hudson PK , Morisseau C , Hammock BD , Pecic S
Ref : Bioorg Chem , 103 :104165 , 2020
Abstract : 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.
ESTHER : Wilt_2020_Bioorg.Chem_103_104165
PubMedSearch : Wilt_2020_Bioorg.Chem_103_104165
PubMedID: 32891856

Title : Novel piperidine-derived amide sEH inhibitors as mediators of lipid metabolism with improved stability - Pecic_2018_Prostaglandins.Other.Lipid.Mediat_136_90
Author(s) : Pecic S , Zeki AA , Xu X , Jin GY , Zhang S , Kodani S , Halim M , Morisseau C , Hammock BD , Deng SX
Ref : Prostaglandins Other Lipid Mediat , 136 :90 , 2018
Abstract : We have previously identified and reported several potent piperidine-derived amide inhibitors of the human soluble epoxide hydrolase (sEH) enzyme. The inhibition of this enzyme leads to elevated levels of epoxyeicosatrienoic acids (EETs), which are known to possess anti-inflammatory, vasodilatory, and anti-fibrotic effects. Herein, we report the synthesis of 9 analogs of the lead sEH inhibitor and the follow-up structure-activity relationship and liver microsome stability studies. Our findings show that isosteric modifications that lead to significant alterations in the steric and electronic properties at a specific position in the molecule can reduce the efficacy by up to 75-fold. On the other hand, substituting hydrogen with deuterium produces a notable increase ( approximately 30%) in the molecules' half-lives in both rat and human microsomes, while maintaining sEH inhibition potency. These data highlight the utility of isosteric replacement for improving bioavailability, and the newly-synthesized inhibitor structures may thus, serve as a starting point for preclinical development. Our docking study reveals that in the catalytic pocket of sEH, these analogs are in proximity of the key amino acids involved in hydrolysis of EETs.
ESTHER : Pecic_2018_Prostaglandins.Other.Lipid.Mediat_136_90
PubMedSearch : Pecic_2018_Prostaglandins.Other.Lipid.Mediat_136_90
PubMedID: 29567338

Title : New therapeutic approaches and novel alternatives for organophosphate toxicity - Katz_2018_Toxicol.Lett_291_1
Author(s) : Katz FS , Pecic S , Schneider L , Zhu Z , Hastings A , Luzac M , MacDonald J , Landry DW , Stojanovic MN
Ref : Toxicol Lett , 291 :1 , 2018
Abstract : Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.
ESTHER : Katz_2018_Toxicol.Lett_291_1
PubMedSearch : Katz_2018_Toxicol.Lett_291_1
PubMedID: 29614332

Title : Cover Picture: Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates (ChemBioChem 15\/2015) - Katz_2015_Chembiochem_16_2113
Author(s) : Katz FS , Pecic S , Tran TH , Trakht I , Schneider L , Zhu Z , Ton-That L , Luzac M , Zlatanic V , Damera S , MacDonald J , Landry DW , Tong L , Stojanovic MN
Ref : Chembiochem , 16 :2113 , 2015
Abstract : The cover picture shows that a mouse exposed to otherwise lethal doses of an organophosphorous agent survives if it is treated with compounds that we recently identified as reactivators of organopsphate-inhibited acetylcholinesterase (AChE). We have demonstrated that survival correlates with reactivation of AChE activity across a panel of tissues, including brain tissues across the blood-brain barrier. We have also determined the co-crystal of one of these reactivators bound to organophosphate-inhibited AChE and found that it binds in a unique manner to the enzyme, forming a dimer within the active site. These compounds were also efficient at reactivating the human form of AChE, thus indicating that their protective effects could be translated for human use. Molecular graphics for the cover were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).
ESTHER : Katz_2015_Chembiochem_16_2113
PubMedSearch : Katz_2015_Chembiochem_16_2113
PubMedID: 26444304

Title : Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates - Katz_2015_Chembiochem_16_2205
Author(s) : Katz FS , Pecic S , Tran TH , Trakht I , Schneider L , Zhu Z , Ton-That L , Luzac M , Zlatanic V , Damera S , MacDonald J , Landry DW , Tong L , Stojanovic MN
Ref : Chembiochem , 16 :2205 , 2015
Abstract : Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups-Mannich phenols and general bases-that are capable of reactivating OPC-inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.
ESTHER : Katz_2015_Chembiochem_16_2205
PubMedSearch : Katz_2015_Chembiochem_16_2205
PubMedID: 26350723
Gene_locus related to this paper: mouse-ACHE

Title : Synthesis and structure-activity relationship of piperidine-derived non-urea soluble epoxide hydrolase inhibitors - Pecic_2013_Bioorg.Med.Chem.Lett_23_417
Author(s) : Pecic S , Pakhomova S , Newcomer ME , Morisseau C , Hammock BD , Zhu Z , Rinderspacher A , Deng SX
Ref : Bioorganic & Medicinal Chemistry Lett , 23 :417 , 2013
Abstract : A series of potent amide non-urea inhibitors of soluble epoxide hydrolase (sEH) is disclosed. The inhibition of soluble epoxide hydrolase leads to elevated levels of epoxyeicosatrienoic acids (EETs), and thus inhibitors of sEH represent one of a novel approach to the development of vasodilatory and anti-inflammatory drugs. Structure-activities studies guided optimization of a lead compound, identified through high-throughput screening, gave rise to sub-nanomolar inhibitors of human sEH with stability in human liver microsomal assay suitable for preclinical development.
ESTHER : Pecic_2013_Bioorg.Med.Chem.Lett_23_417
PubMedSearch : Pecic_2013_Bioorg.Med.Chem.Lett_23_417
PubMedID: 23237835
Gene_locus related to this paper: human-EPHX2

Title : Design, synthesis and evaluation of non-urea inhibitors of soluble epoxide hydrolase - Pecic_2012_Bioorg.Med.Chem.Lett_22_601
Author(s) : Pecic S , Deng SX , Morisseau C , Hammock BD , Landry DW
Ref : Bioorganic & Medicinal Chemistry Lett , 22 :601 , 2012
Abstract : Inhibition of soluble epoxide hydrolase (sEH) has been proposed as a new pharmaceutical approach for treating hypertension and vascular inflammation. The most potent sEH inhibitors reported in literature to date are urea derivatives. However, these compounds have limited pharmacokinetic profiles. We investigated non-urea amide derivatives as sEH inhibitors and identified a potent human sEH inhibitor 14-34 having potency comparable to urea-based inhibitors.
ESTHER : Pecic_2012_Bioorg.Med.Chem.Lett_22_601
PubMedSearch : Pecic_2012_Bioorg.Med.Chem.Lett_22_601
PubMedID: 22079754