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1.
J Med Chem ; 61(5): 2041-2051, 2018 03 08.
Article in English | MEDLINE | ID: mdl-29425457

ABSTRACT

Two 2-aminoimidazole-based inhibitors, LY3031207 (1) and LY3023703 (2), of the microsomal prostaglandin E synthase-1 (mPGES-1) enzyme were found to cause drug-induced liver injury (DILI) in humans. We studied imidazole ring substitutions to successfully mitigate reactive metabolite (RM) formation. These studies support the conclusion that RM formation may play a role in the observations of DILI and the consideration of 2-aminoimidazoles as structure alerts, due to the high likelihood of bioactivation to generate RMs.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Imidazoles/pharmacology , Prostaglandin-E Synthases/antagonists & inhibitors , Humans , Imidazoles/adverse effects , Imidazoles/metabolism , Safety-Based Drug Withdrawals , Structure-Activity Relationship
2.
Pharmacol Res Perspect ; 5(3): e00316, 2017 06.
Article in English | MEDLINE | ID: mdl-28603634

ABSTRACT

Prostaglandin (PG) E2 is the key driver of inflammation associated with arthritic conditions. Inhibitors of PGE 2 production (NSAIDs and Coxibs) are used to treat these conditions, but carry significant side effect risks due to the inhibition of all prostanoids that play important physiological function. The activities of PGE 2 are transduced through various receptor sub-types. Prostaglandin E2 type 4 receptor (EP4) is associated with the development of inflammation and autoimmunity. We therefore are interested in identifying novel EP4 antagonists to treat the signs and symptoms of arthritis without the potential side effects of PGE 2 modulators such as NSAIDs and Coxibs. Novel EP4 antagonists representing distinct chemical scaffolds were identified using a variety of in vitro functional assays and were shown to be selective and potent. The compounds were shown to be efficacious in animal models of analgesia, inflammation, and arthritis.

3.
Bioorg Med Chem Lett ; 27(6): 1478-1483, 2017 03 15.
Article in English | MEDLINE | ID: mdl-28190634

ABSTRACT

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.


Subject(s)
Benzoates/chemistry , Benzoates/pharmacology , Drug Discovery , Microsomes/drug effects , Prostaglandin-E Synthases/antagonists & inhibitors , Animals , Crystallography, X-Ray , Dogs , Microsomes/enzymology , Prostaglandin-E Synthases/chemistry , Rats
4.
Bioorg Med Chem Lett ; 26(19): 4824-4828, 2016 10 01.
Article in English | MEDLINE | ID: mdl-27554445

ABSTRACT

Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30µM, and failed to inhibit human mPGES-2 at 62.5µM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.


Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Prostaglandin-E Synthases/antagonists & inhibitors , A549 Cells , Animals , Crystallography, X-Ray , Dogs , Humans , Piperidines/pharmacokinetics , Rats , Species Specificity , Structure-Activity Relationship
5.
Bioorg Med Chem Lett ; 26(9): 2303-7, 2016 May 01.
Article in English | MEDLINE | ID: mdl-27020304

ABSTRACT

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.


Subject(s)
Benzoates/pharmacology , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Animals , Benzoates/chemistry , Rats , X-Ray Diffraction
6.
J Med Chem ; 59(1): 194-205, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26653180

ABSTRACT

As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 µM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Intramolecular Oxidoreductases/antagonists & inhibitors , Microsomes/enzymology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Biological Availability , Celecoxib/pharmacology , Cyclooxygenase Inhibitors/pharmacokinetics , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme Inhibitors/chemical synthesis , Cytochrome P-450 Enzyme Inhibitors/pharmacology , Dogs , Drug Discovery , Humans , Microsomes/drug effects , Models, Molecular , Prostaglandin-E Synthases , Rats , Structure-Activity Relationship
7.
Bioorg Med Chem Lett ; 25(16): 3176-8, 2015 Aug 15.
Article in English | MEDLINE | ID: mdl-26091726

ABSTRACT

EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.


Subject(s)
Analgesics/chemistry , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Analgesics/metabolism , Analgesics/pharmacokinetics , Animals , Blood Cells/cytology , Blood Cells/drug effects , Blood Cells/metabolism , Dogs , Half-Life , Humans , Lipopolysaccharides/toxicity , Protein Binding , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/metabolism
8.
J Med Chem ; 58(11): 4727-37, 2015 Jun 11.
Article in English | MEDLINE | ID: mdl-25961169

ABSTRACT

Microsomal prostaglandin E synthase 1 (mPGES-1) is an α-helical homotrimeric integral membrane inducible enzyme that catalyzes the formation of prostaglandin E2 (PGE2) from prostaglandin H2 (PGH2). Inhibition of mPGES-1 has been proposed as a therapeutic strategy for the treatment of pain, inflammation, and some cancers. Interest in mPGES-1 inhibition can, in part, be attributed to the potential circumvention of cardiovascular risks associated with anti-inflammatory cyclooxygenase 2 inhibitors (coxibs) by targeting the prostaglandin pathway downstream of PGH2 synthesis and avoiding suppression of antithrombotic prostacyclin production. We determined the crystal structure of mPGES-1 bound to four potent inhibitors in order to understand their structure-activity relationships and provide a framework for the rational design of improved molecules. In addition, we developed a light-scattering-based thermal stability assay to identify molecules for crystallographic studies.


Subject(s)
Analgesics/chemistry , Anti-Inflammatory Agents/chemistry , Drug Design , Enzyme Inhibitors/chemistry , Imidazoles/chemistry , Intramolecular Oxidoreductases/chemistry , Amino Acid Sequence , Analgesics/metabolism , Analgesics/therapeutic use , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/therapeutic use , Crystallography, X-Ray , Enzyme Inhibitors/metabolism , Humans , Intramolecular Oxidoreductases/metabolism , Microsomes/enzymology , Models, Molecular , Molecular Sequence Data , Molecular Structure , Prostaglandin-E Synthases , Protein Conformation , Sequence Homology, Amino Acid
9.
Eur J Nucl Med Mol Imaging ; 40(2): 245-53, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23135321

ABSTRACT

PURPOSE: Two allosteric modulators of the group I metabotropic glutamate receptors (mGluR1 and mGluR5) were evaluated as positron emission tomography (PET) radioligands for mGluR1. METHODS: LY2428703, a full mGluR1 antagonist (IC(50) 8.9 nM) and partial mGluR5 antagonist (IC(50) 118 nM), and LSN2606428, a full mGluR1 and mGluR5 antagonist (IC(50) 35.3 nM and 10.2 nM, respectively) were successfully labeled with (11)C and evaluated as radioligands for mGluR1. The pharmacology of LY2428703 was comprehensively assessed in vitro and in vivo, and its biodistribution was investigated by liquid chromatography-mass spectrometry/mass spectrometry, and by PET imaging in the rat. In contrast, LSN2606428 was only evaluated in vitro; further evaluation was stopped due to its unfavorable pharmacological properties and binding affinity. RESULTS: (11)C-LY2428703 showed promising characteristics, including: (1) high potency for binding to human mGluR1 (IC(50) 8.9 nM) with no significant affinity for other human mGlu receptors (mGluR2 through mGluR8); (2) binding to brain displaceable by administration of an mGluR1 antagonist; (3) only one major radiometabolite in both plasma and brain, with a negligible brain concentration (with 3.5 % of the total radioactivity in cerebellum) and no receptor affinity; (4) a large specific and displaceable signal in the mGluR1-rich cerebellum with no significant in vivo affinity for mGluR5, as shown by PET studies in rats; and (5) lack of substrate behavior for efflux transporters at the blood-brain barrier, as shown by PET studies conducted in wild-type and knockout mice. CONCLUSION: (11)C-LY2428703, a new PET radioligand for mGluR1 quantification, displayed promising characteristics both in vitro and in vivo in rodents.


Subject(s)
Brain/pathology , Carbon Isotopes/pharmacology , Positron-Emission Tomography/methods , Receptors, Metabotropic Glutamate/metabolism , Allosteric Site , Animals , Blood-Brain Barrier , Chromatography, Liquid/methods , Humans , In Vitro Techniques , Inhibitory Concentration 50 , Ligands , Male , Mice , Mice, Knockout , Models, Chemical , Rats , Spectrometry, Mass, Electrospray Ionization/methods , Tandem Mass Spectrometry/methods
10.
Bioorg Med Chem Lett ; 22(7): 2514-7, 2012 Apr 01.
Article in English | MEDLINE | ID: mdl-22386665

ABSTRACT

The disclosed 3-phenyl-5-isothiazole carboxamides are potent allosteric antagonists of mGluR1 with generally good selectivity relative to the related group 1 receptor mGluR5. Pharmacokinetic properties of a member of this series (1R,2R)-N-(3-(4-methoxyphenyl)-4-methylisothiazol-5-yl)-2-methylcyclopropanecarboxamide (14) are good, showing acceptable plasma and brain exposure after oral dosing. Oral administration of isothiazole 14 gave robust activity in the formalin model of persistent pain which correlated with CNS receptor occupancy.


Subject(s)
Amides/chemical synthesis , Analgesics/chemical synthesis , Excitatory Amino Acid Antagonists/chemical synthesis , Pain/drug therapy , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Thiazoles/chemical synthesis , Administration, Oral , Amides/administration & dosage , Amides/pharmacokinetics , Analgesics/administration & dosage , Analgesics/pharmacokinetics , Animals , Biological Availability , Brain/metabolism , Excitatory Amino Acid Antagonists/administration & dosage , Excitatory Amino Acid Antagonists/pharmacokinetics , Humans , Pain/metabolism , Pain Measurement , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Stereoisomerism , Structure-Activity Relationship , Thiazoles/administration & dosage , Thiazoles/pharmacokinetics
11.
Bioorg Med Chem Lett ; 16(14): 3843-6, 2006 Jul 15.
Article in English | MEDLINE | ID: mdl-16697186

ABSTRACT

Homologation and cyclization back to the chiral methine of compound 3 yields achiral 4,4-disubstituted piperidine privileged structures (e.g., 8a) useful in the construction of melanocortin 4 receptor (MC4R) ligands. The piperidine nitrogen was replaced with carbon, oxygen, sulfur, and sulfone with minor erosion of binding. The methyl cyclohexane substituent was the most potent while significant affinity was still seen for smaller lipophilic groups such as ethyl.


Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptor, Melanocortin, Type 4/metabolism , Binding Sites , Carbon/chemistry , Cyclohexanes/chemistry , Ligands , Oxygen/chemistry , Receptor, Melanocortin, Type 4/antagonists & inhibitors , Structure-Activity Relationship , Sulfones/chemistry , Sulfur/chemistry
12.
Bioorg Med Chem Lett ; 16(13): 3449-53, 2006 Jul 01.
Article in English | MEDLINE | ID: mdl-16650763

ABSTRACT

Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.


Subject(s)
Piperazines/chemistry , Piperazines/pharmacology , Receptor, Melanocortin, Type 4/drug effects , Ligands , Molecular Structure , Piperazines/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Stereoisomerism , Structure-Activity Relationship
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