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1.
ACS Med Chem Lett ; 10(3): 267-272, 2019 Mar 14.
Article in English | MEDLINE | ID: mdl-30891124

ABSTRACT

This report discloses the discovery and characterization of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as selective negative modulators of α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPARs) associated with transmembrane AMPAR regulatory protein γ-8. Imidazopyrazine 5 was initially identified as a promising γ-8 selective high-throughput screening hit, and subsequent structure-activity relationship optimization yielded subnanomolar, brain penetrant leads. Replacement of the imidazopyrazine core with an isosteric pyrazolopyrimidine scaffold improved microsomal stability and efflux liabilities to provide 26, JNJ-61432059. Following oral administration, 26 exhibited time- and dose-dependent AMPAR/γ-8 receptor occupancy in mouse hippocampus, which resulted in robust seizure protection in corneal kindling and pentylenetetrazole (PTZ) anticonvulsant models.

2.
ACS Med Chem Lett ; 9(8): 821-826, 2018 Aug 09.
Article in English | MEDLINE | ID: mdl-30128074

ABSTRACT

Glutamate mediates fast excitatory neurotransmission via ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The trafficking and gating properties of AMPA receptors (AMPARs) can be amplified by transmembrane AMPAR regulatory proteins (TARPs), which are often expressed in localized brain regions. Herein, we describe the discovery, lead optimization, and preclinical characterization of 5-arylbenzimidazolone and oxindole-based negative modulators of AMPARs associated with TARP γ-8, the primary TARP found in hippocampus. High-throughput screen lead 4 was optimized for potency and brain penetration to provide benzimidazolone 3, JNJ-55511118.1 Replacement of the benzimidazolone core in 3 with an oxindole mitigated reactive metabolite formation and led to the identification of 18 (GluA1/γ-8 pIC50 = 9.7). Following oral dosing in rats, 18 demonstrated robust target engagement in hippocampus as assessed by ex vivo autoradiography (ED50 = 0.6 mg/kg, plasma EC50 = 9 ng/mL).

3.
J Med Chem ; 60(11): 4559-4572, 2017 06 08.
Article in English | MEDLINE | ID: mdl-28493698

ABSTRACT

The synthesis and preclinical characterization of novel 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are potent and selective brain penetrant P2X7 antagonists are described. Optimization efforts based on previously disclosed unsubstituted 6,7-dihydro-4H-triazolo[4,5-c]pyridines, methyl substituted 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazines, and several other series lead to the identification of a series of 4-(R)-methyl-6,7-dihydro-4H-triazolo[4,5-c]pyridines that are selective P2X7 antagonists with potency at the rodent and human P2X7 ion channels. These novel P2X7 antagonists have suitable physicochemical properties, and several analogs have an excellent pharmacokinetic profile, good partitioning into the CNS and show robust in vivo target engagement after oral dosing. Improvements in metabolic stability led to the identification of JNJ-54175446 (14) as a candidate for clinical development. The drug discovery efforts and strategies that resulted in the identification of the clinical candidate are described herein.


Subject(s)
Purinergic P2X Receptor Antagonists/pharmacology , Pyridines/pharmacology , Receptors, Purinergic P2X7/drug effects , Animals , Biological Availability , Humans , Purinergic P2X Receptor Antagonists/pharmacokinetics
4.
Handb Exp Pharmacol ; 241: 301-320, 2017.
Article in English | MEDLINE | ID: mdl-28233185

ABSTRACT

The discovery of the histamine H4 receptor (H4R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H4R relative to other histamine receptors. The discovery of the selective H4R antagonist JNJ 7777120 was vital for showing a role for the H4R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H4R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H4R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H4R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H4R antagonists can be beneficial in treating atopic dermatitis and pruritus.


Subject(s)
Histamine Antagonists/pharmacology , Histamine Antagonists/therapeutic use , Histamine/metabolism , Receptors, Histamine/metabolism , Animals , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/metabolism , Humans
5.
J Med Chem ; 59(18): 8535-48, 2016 09 22.
Article in English | MEDLINE | ID: mdl-27548392

ABSTRACT

The synthesis and SAR of a series of 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine P2X7 antagonists are described. Addressing P2X7 affinity and liver microsomal stability issues encountered with this template afforded methyl substituted 4,5,6,7-tetrahydro-imidazo[4,5-c]pyridines ultimately leading to the identification of 1 (JNJ 54166060). 1 is a potent P2X7 antagonist with an ED50 = 2.3 mg/kg in rats, high oral bioavailability and low-moderate clearance in preclinical species, acceptable safety margins in rats, and a predicted human dose of 120 mg of QD. Additionally, 1 possesses a unique CYP profile and was found to be a regioselective inhibitor of midazolam CYP3A metabolism.


Subject(s)
Purinergic P2X Receptor Antagonists/chemistry , Purinergic P2X Receptor Antagonists/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptors, Purinergic P2X7/metabolism , Administration, Oral , Animals , Dogs , Halogenation , Haplorhini , Humans , Imidazoles/administration & dosage , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Mice , Models, Molecular , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Rats
7.
Bioorg Med Chem Lett ; 26(16): 3838-45, 2016 08 15.
Article in English | MEDLINE | ID: mdl-27426304

ABSTRACT

The P2X7 receptor is an ATP-gated nonselective cation channel that has been linked to a number of inflammatory diseases. Activation of the P2X7 receptor by elevated levels of ATP results in the release of proinflammatory cytokines and elevated levels of these cytokines has been associated with a variety of disease states. A number of research groups in both industry and academia have explored the identification of P2X7R antagonists as therapeutic agents. Much of this early effort focused on the treatment of diseases related to peripheral inflammation and resulted in several clinical candidates, none of which were advanced to market. The emerging role of the P2X7 receptor in neuroinflammation and related diseases has resulted in a shift in medicinal chemistry efforts toward the development of centrally penetrant antagonists. This review will highlight the biology supporting the role of P2X7 in diseases related to neuroinflammation and review the recent medicinal chemistry efforts to identify centrally penetrant antagonists.


Subject(s)
Purinergic P2X Receptor Antagonists/chemistry , Receptors, Purinergic P2X7/metabolism , Animals , Central Nervous System Diseases/drug therapy , Central Nervous System Diseases/metabolism , Clinical Trials as Topic , Cytokines/metabolism , Half-Life , Humans , Inflammation/prevention & control , Protein Binding , Purinergic P2X Receptor Antagonists/pharmacokinetics , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic P2X7/chemistry
8.
J Pharmacol Exp Ther ; 357(2): 394-414, 2016 May.
Article in English | MEDLINE | ID: mdl-26989142

ABSTRACT

Members of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA) subtype of ionotropic glutamate receptors mediate the majority of fast synaptic transmission within the mammalian brain and spinal cord, representing attractive targets for therapeutic intervention. Here, we describe novel AMPA receptor modulators that require the presence of the accessory protein CACNG8, also known as transmembrane AMPA receptor regulatory protein γ8 (TARP-γ8). Using calcium flux, radioligand binding, and electrophysiological assays of wild-type and mutant forms of TARP-γ8, we demonstrate that these compounds possess a novel mechanism of action consistent with a partial disruption of the interaction between the TARP and the pore-forming subunit of the channel. One of the molecules, 5-[2-chloro-6-(trifluoromethoxy)phenyl]-1,3-dihydrobenzimidazol-2-one (JNJ-55511118), had excellent pharmacokinetic properties and achieved high receptor occupancy following oral administration. This molecule showed strong, dose-dependent inhibition of neurotransmission within the hippocampus, and a strong anticonvulsant effect. At high levels of receptor occupancy in rodent in vivo models, JNJ-55511118 showed a strong reduction in certain bands on electroencephalogram, transient hyperlocomotion, no motor impairment on rotarod, and a mild impairment in learning and memory. JNJ-55511118 is a novel tool for reversible AMPA receptor inhibition, particularly within the hippocampus, with potential therapeutic utility as an anticonvulsant or neuroprotectant. The existence of a molecule with this mechanism of action demonstrates the possibility of pharmacological targeting of accessory proteins, increasing the potential number of druggable targets.


Subject(s)
Benzimidazoles/therapeutic use , Calcium Channels/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Receptors, AMPA/drug effects , Animals , Calcium Channels/genetics , Calcium Signaling/drug effects , Drug Design , Electroencephalography/drug effects , HEK293 Cells , Humans , Learning/drug effects , Memory/drug effects , Mice, Inbred C57BL , Mice, Knockout , Motor Activity/drug effects , Mutation/genetics , Neurons/drug effects , Postural Balance/drug effects , Rats, Sprague-Dawley , Receptors, AMPA/genetics
9.
Bioorg Med Chem Lett ; 26(2): 257-261, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26707399

ABSTRACT

The synthesis, SAR, and preclinical characterization of a series of substituted 6,7-dihydro[1,2,4]triazolo[4,3]pyrazin-8(5H)-one P2X7 receptor antagonists are described. Optimized leads from this series comprise some of the most potent human P2X7R antagonists reported to date (IC50s<1nM). They also exhibit sufficient potency and oral bioavailability in rat to enable extensive in vivo profiling. Although many of the disclosed compounds are peripherally restricted, compound 11d is brain penetrant and upon oral administration demonstrated dose-dependent target engagement in rat hippocampus as determined by ex vivo receptor occupancy with radiotracer 5 (ED50=0.8mg/kg).


Subject(s)
Central Nervous System Agents/pharmacology , Purinergic P2X Receptor Antagonists/pharmacology , Pyrazines/pharmacology , Triazoles/pharmacology , Animals , Blood-Brain Barrier/metabolism , Caco-2 Cells , Central Nervous System Agents/chemical synthesis , Central Nervous System Agents/pharmacokinetics , Hippocampus/metabolism , Humans , Microsomes, Liver/metabolism , Purinergic P2X Receptor Antagonists/chemical synthesis , Purinergic P2X Receptor Antagonists/pharmacokinetics , Pyrazines/chemical synthesis , Pyrazines/pharmacokinetics , Rats , Receptors, Purinergic P2X7/metabolism , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/pharmacokinetics , Tritium
10.
J Org Chem ; 80(21): 11003-12, 2015 Nov 06.
Article in English | MEDLINE | ID: mdl-26458051

ABSTRACT

We report a Cu(I)-catalyzed azide-alkyne-allyl halide three-component reaction for a one-pot synthesis of 1,4-disubstituted 5-allyl-1,2,3-triazoles. The allyl moiety provides not only the electrophile but also a coordinating ligand to Cu, which is essential for the reaction to occur under mild conditions. A concise synthesis of a potential drug candidate 1 is realized based on this key reaction.

11.
ACS Med Chem Lett ; 6(6): 671-6, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-26101572

ABSTRACT

We describe the synthesis and SAR of 1,2,3-triazolopiperidines as a novel series of potent, brain penetrant P2X7 antagonists. Initial efforts yielded a series of potent human P2X7R antagonists with moderate to weak rodent potency, some CYP inhibition, poor metabolic stability, and low solubility. Further work in this series, which focused on the SAR of the N-linked heterocycle, not only increased the potency at the human P2X7R but also provided compounds with good potency at the rat P2X7R. These efforts eventually delivered a potent rat and human P2X7R antagonist with good physicochemical properties, an excellent pharmacokinetic profile, good partitioning into the CNS, and demonstrated in vivo target engagement after oral dosing.

12.
J Med Chem ; 58(18): 7119-27, 2015 Sep 24.
Article in English | MEDLINE | ID: mdl-25993395

ABSTRACT

Histamine is an important endogenous signaling molecule that is involved in a number of physiological processes including allergic reactions, gastric acid secretion, neurotransmitter release, and inflammation. The biological effects of histamine are mediated by four histamine receptors with distinct functions and distribution profiles (H1-H4). The most recently discovered histamine receptor (H4) has emerged as a promising drug target for treating inflammatory diseases. A detailed understanding of the role of the H4 receptor in human disease remains elusive, in part because low sequence similarity between the human and rodent H4 receptors complicates the translation of preclinical pharmacology to humans. This review provides an overview of H4 drug discovery programs that have studied cross-species structure-activity relationships, with a focus on the functional profiling of the 2-aminopyrimidine chemotype that has advanced to the clinic for allergy, atopic dermatitis, asthma, and rheumatoid arthritis.


Subject(s)
Aminopyridines/chemistry , Histamine Agonists/chemistry , Histamine Antagonists/chemistry , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine/metabolism , Aminopyridines/pharmacology , Aminopyridines/therapeutic use , Animals , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Asthma/drug therapy , Asthma/metabolism , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/metabolism , Drug Partial Agonism , Histamine Agonists/pharmacology , Histamine Agonists/therapeutic use , Histamine Antagonists/pharmacology , Histamine Antagonists/therapeutic use , Humans , Hypersensitivity/drug therapy , Hypersensitivity/metabolism , Receptors, Histamine H4 , Structure-Activity Relationship
13.
Bioorg Med Chem Lett ; 25(4): 956-9, 2015 Feb 15.
Article in English | MEDLINE | ID: mdl-25595684

ABSTRACT

Previously disclosed H4 receptor modulators, the triamino substituted pyridines and pyrimidines, contain a free primary amino (-NH2) group. In this Letter we demonstrate that an exocyclic amine (NH2) is not needed to maintain affinity, and also show a significant divergence in the SAR of the pendant diamine component. These des-NH2 azacycles also show a distinct functional spectrum, that appears to be influenced by the diamine component; in the case of the 1,3-amino pyrimidines, the preferred diamine is the amino pyrrolidine instead of the more common piperazines. Finally, we introduce 3,5-diamino pyridazines as novel histamine H4 antagonists.


Subject(s)
Pyridines/pharmacology , Receptors, G-Protein-Coupled/drug effects , Receptors, Histamine/drug effects , Humans , Pyridines/chemistry , Receptors, Histamine H4
14.
Bioorg Med Chem Lett ; 24(23): 5489-92, 2014 Dec 01.
Article in English | MEDLINE | ID: mdl-25455490

ABSTRACT

During the course of our efforts toward the discovery of human histamine H4 antagonists from a series of 2-aminiopyrimidines, it was noted that a 6-trifluoromethyl group dramatically reduced affinity of the series toward the histamine H4 receptor. This observation was further investigated by synthesizing a series of ligands that varied in pKa of the pyrimidine derived H4 ligands by over five orders of magnitude and the effect on histamine H4 affinity. This trend was then extended to the discovery of C-linked piperidinyl-2-amino pyridines as histamine H4 receptor antagonists.


Subject(s)
Histamine Antagonists/pharmacokinetics , Pyridines/chemistry , Pyrimidines/chemistry , Receptors, G-Protein-Coupled/drug effects , Receptors, Histamine/drug effects , Histamine Antagonists/therapeutic use , Humans , Ligands , Molecular Structure , Receptors, Histamine H4
15.
J Med Chem ; 57(6): 2429-39, 2014 Mar 27.
Article in English | MEDLINE | ID: mdl-24495018

ABSTRACT

This report discloses the discovery and SAR of a series of 6-alkyl-2-aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4-diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects.


Subject(s)
Histamine Antagonists/chemical synthesis , Histamine Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Arthritis/chemically induced , Arthritis/prevention & control , Collagen , Dogs , Drug Design , Drug Discovery , Histamine , Indicators and Reagents , Lipopolysaccharides/pharmacology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Molecular , Pruritus/chemically induced , Pruritus/prevention & control , Rats , Rats, Sprague-Dawley , Receptors, Histamine , Receptors, Histamine H4 , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/biosynthesis
16.
Bioorg Med Chem Lett ; 23(3): 811-5, 2013 Feb 01.
Article in English | MEDLINE | ID: mdl-23260350

ABSTRACT

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).


Subject(s)
Benzofurans/chemistry , Enzyme Inhibitors/chemistry , Epoxide Hydrolases/antagonists & inhibitors , Animals , Benzofurans/pharmacology , Dose-Response Relationship, Drug , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Mice , Molecular Structure , Rats , Rats, Sprague-Dawley
17.
Bioorg Med Chem Lett ; 21(21): 6577-81, 2011 Nov 01.
Article in English | MEDLINE | ID: mdl-21920744

ABSTRACT

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.


Subject(s)
Histamine Antagonists/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Animals , Histamine Antagonists/chemistry , Mice , Receptors, Histamine , Receptors, Histamine H4
18.
Bioorg Med Chem Lett ; 21(10): 3113-6, 2011 May 15.
Article in English | MEDLINE | ID: mdl-21458260

ABSTRACT

Two series of triamino pyrimidines and a series of triamino pyridines have been synthesized and their structure-activity relationships evaluated for activity at the H(4) receptor in competitive binding and functional assays. Small structural changes in these three hetereoaromatic cores influenced the functional activity of these compounds.


Subject(s)
Pyridines/pharmacology , Pyrimidines/pharmacology , Receptors, G-Protein-Coupled/antagonists & inhibitors , Amines/chemistry , Binding, Competitive , Biological Assay , Humans , Inhibitory Concentration 50 , Molecular Structure , Protein Binding/drug effects , Pyridines/chemical synthesis , Pyridines/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Receptors, Histamine , Receptors, Histamine H4 , Structure-Activity Relationship
19.
Bioorg Med Chem Lett ; 20(11): 3367-71, 2010 Jun 01.
Article in English | MEDLINE | ID: mdl-20452213

ABSTRACT

The present work details the transformation of a series of human histamine H(4) agonists into potent functional antagonists. Replacement of the aminopyrrolidine diamine functionality with a 5,6-fused pyrrolopiperidine ring system led to an antagonist. The dissection of this fused diamine led to the eventual replacement with heterocycles. The incorporation of histamine as the terminal amine led to a very potent and selective histamine H(4) agonist; whereas incorporation of the constrained histamine analog, spinacamine, modulated the functional activity to give a partial agonist. In two separate series, we demonstrate that constraining the terminal amino portion modulated the spectrum of functional activity of histamine H(4) ligands.


Subject(s)
Benzimidazoles/pharmacology , Histamine Agonists/pharmacology , Histamine Antagonists/pharmacology , Receptors, G-Protein-Coupled/drug effects , Receptors, Histamine/drug effects , Benzimidazoles/chemistry , Histamine Agonists/chemistry , Histamine Antagonists/chemistry , Humans , Ligands , Receptors, G-Protein-Coupled/metabolism , Receptors, Histamine/metabolism , Receptors, Histamine H4 , Structure-Activity Relationship
20.
J Med Chem ; 51(14): 4150-69, 2008 Jul 24.
Article in English | MEDLINE | ID: mdl-18588282

ABSTRACT

LTA 4H is a ubiquitously distributed 69 kDa zinc-containing cytosolic enzyme with both hydrolase and aminopeptidase activity. As a hydrolase, LTA 4H stereospecifically catalyzes the transformation of the unstable epoxide LTA 4 to the diol LTB 4, a potent chemoattractant and activator of neutrophils and a chemoattractant of eosinophils, macrophages, mast cells, and T cells. Inhibiting the formation of LTB 4 is expected to be beneficial in the treatment of inflammatory diseases such as inflammatory bowel disease (IBD), asthma, and atherosclerosis. We developed a pharmacophore model using a known inhibitor manually docked into the active site of LTA 4H to identify a subset of compounds for screening. From this work we identified a series of benzoxazole, benzthiazole, and benzimidazole inhibitors. SAR studies resulted in the identification of several potent inhibitors with an appropriate cross-reactivity profile and excellent PK/PD properties. Our efforts focused on further profiling JNJ 27265732, which showed encouraging efficacy in a disease model relevant to IBD.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Enzyme Inhibitors/pharmacology , Epoxide Hydrolases/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Catalysis , Dogs , Drug Evaluation, Preclinical , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Humans , Magnetic Resonance Spectroscopy , Mice , Structure-Activity Relationship
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