ABSTRACT
PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4CRBN, and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.
ABSTRACT
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability (t1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.
Subject(s)
Ferroptosis , Neoplasms , Mice , Animals , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Biological AvailabilityABSTRACT
The voltage-gated sodium channel Nav1.7 is an attractive target for the treatment of pain based on the high level of target validation with genetic evidence linking Nav1.7 to pain in humans. Our effort to identify selective, CNS-penetrant Nav1.7 blockers with oral activity, improved selectivity, good drug-like properties, and safety led to the discovery of 2-substituted quinolines and quinolones as potent small molecule Nav1.7 blockers. The design of these molecules focused on maintaining potency at Nav1.7, improving selectivity over the hERG channel, and overcoming phospholipidosis observed with the initial leads. The structure-activity relationship (SAR) studies leading to the discovery of (R)-(3-fluoropyrrolidin-1-yl)(6-((5-(trifluoromethyl)pyridin-2-yl)oxy)quinolin-2-yl)methanone (ABBV-318) are described herein. ABBV-318 displayed robust in vivo efficacy in both inflammatory and neuropathic rodent models of pain. ABBV-318 also inhibited Nav1.8, another sodium channel isoform that is an active target for the development of new pain treatments.
Subject(s)
Pain , Sodium Channels , Humans , Pain/drug therapy , Pain Management , Protein Isoforms , Sodium Channels/metabolism , Structure-Activity RelationshipABSTRACT
Foxp3+ regulatory T cells (Tregs) represent a major fraction of skin resident T cells. Although normally protective, Tregs have been shown to produce pro-inflammatory cytokines in human diseases, including psoriasis. A significant hurdle in the Treg field has been the identification, or development, of model systems to study this Treg plasticity. To overcome this gap, we analyzed skin resident Tregs in a mouse model of IL-23 mediated psoriasiform dermatitis. Our results demonstrate that IL-23 drove the accumulation of Tregs; including a subpopulation that co-expressed RORγt and produced IL-17A. Genesis of this population was attenuated by a RORγt inverse agonist compound and clinically relevant therapeutics. In vitro, IL-23 drove the generation of CD4+Foxp3+RORγt+IL-17A+ cells from Treg cells. Collectively, our data shows that IL-23 drives Treg plasticity by inducing a population of CD4+Foxp3+RORγt+IL-17A+ cells that could play a role in the disease pathogenesis. Through this work, we define an in vitro system and a pre-clinical in vivo mouse model that can be used to further study Treg homeostasis and plasticity in the context of psoriasis.
Subject(s)
Cell Plasticity/drug effects , Dermatitis/metabolism , Interleukin-23/pharmacology , Psoriasis/metabolism , T-Lymphocytes, Regulatory/metabolism , Animals , Cells, Cultured , Dermatitis/pathology , Disease Models, Animal , Forkhead Transcription Factors/metabolism , Interleukin-17/metabolism , Interleukin-23/administration & dosage , Mice , Mice, Inbred C57BL , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Psoriasis/chemically induced , Psoriasis/pathology , T-Lymphocytes, Regulatory/drug effectsABSTRACT
Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORγt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORγt+ cells, and inhibition of RORγt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Interleukin-23/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Piperidines/pharmacology , Psoriasis/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , COS Cells , Cells, Cultured , Chlorocebus aethiops , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Piperidines/therapeutic useABSTRACT
A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.
Subject(s)
Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry , Quinolines/chemistry , Animals , Disease Models, Animal , Humans , MiceABSTRACT
Transient receptor potential vanilloid 3 (TRPV3) is a Ca(2+)- and Na(+)-permeable channel with a unique expression pattern. TRPV3 is found in both neuronal and non-neuronal tissues, including dorsal root ganglia, spinal cord, and keratinocytes. Recent studies suggest that TRPV3 may play a role in inflammation, pain sensation, and skin disorders. TRPV3 studies have been challenging, in part due to a lack of research tools such as selective antagonists. Herein, we provide the first detailed report on the development of potent and selective TRPV3 antagonists featuring a pyridinyl methanol moiety. Systematic optimization of pharmacological, physicochemical, and ADME properties of original lead 5a resulted in identification of a novel and selective TRPV3 antagonist 74a, which demonstrated a favorable preclinical profile in two different models of neuropathic pain as well as in a reserpine model of central pain.
Subject(s)
Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Calcium/metabolism , Cyclobutanes/chemistry , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Molecular Conformation , Pyridines/chemistry , Structure-Activity Relationship , TRPV Cation Channels/metabolismABSTRACT
The genetic validation for the role of the Nav1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.
Subject(s)
Analgesics/pharmacology , Imidazolidines/pharmacology , Indazoles/pharmacology , NAV1.7 Voltage-Gated Sodium Channel/chemistry , Osteoarthritis/drug therapy , Pain/drug therapy , Pyrroles/pharmacology , Sodium Channel Blockers/pharmacology , Analgesics/chemistry , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophysiology , Evoked Potentials , Imidazolidines/chemistry , Indazoles/chemistry , Iodoacetic Acid/toxicity , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel/metabolism , Osteoarthritis/chemically induced , Osteoarthritis/metabolism , Pain/metabolism , Pain/pathology , Pain Measurement , Pyrroles/chemistry , Rats , Sodium Channel Blockers/chemistry , Structure-Activity RelationshipABSTRACT
Transient receptor potential vanilloid 1 (TRPV1) is a multifunctional ion channel playing important roles in a numerous biological processes including the regulation of body temperature. Within distinct and tight chemical space of chromanyl ureas TRPV1 ligands were identified that exhibit distinctive pharmacology and a spectrum of thermoregulatory effects ranging from hypothermia to hyperthermia. The ability to manipulate these effects by subtle structural modifications of chromanyl ureas may serve as a productive approach in TRPV1 drug discovery programs addressing either side effect or desired target profiles of the compounds. Because chromanyl ureas in the TRPV1 context are generally antagonists, we verified observed partial agonist effects of a subset of compounds within that chemotype by comparing the in vitro profile of Compound 3 with known partial agonist 5'-I-RTX.
ABSTRACT
The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.
Subject(s)
Analgesics/chemistry , Body Temperature/drug effects , TRPV Cation Channels/antagonists & inhibitors , Urea/chemistry , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Area Under Curve , Body Temperature/physiology , Dogs , Dose-Response Relationship, Drug , Drug Discovery , HEK293 Cells , Humans , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Metabolic Clearance Rate , Models, Chemical , Molecular Structure , Rats , Structure-Activity Relationship , TRPV Cation Channels/chemistry , TRPV Cation Channels/metabolism , Urea/analogs & derivatives , Urea/pharmacokinetics , Urea/pharmacologyABSTRACT
The rodent transient receptor potential ankyrin-1 (TRPA1) channel has been hypothesized to serve as a temperature sensor for thermoregulation in the cold. We tested this hypothesis by using deletion of the Trpa1 gene in mice and pharmacological blockade of the TRPA1 channel in rats. In both Trpa1(-/-) and Trpa1(+/+) mice, severe cold exposure (8°C) resulted in decreases of skin and deep body temperatures to â¼8°C and 13°C, respectively, both temperatures being below the reported 17°C threshold temperature for TRPA1 activation. Under these conditions, Trpa1(-/-) mice had the same dynamics of body temperature as Trpa1(+/+) mice and showed no weakness in the tail skin vasoconstriction response or thermogenic response to cold. In rats, the effects of pharmacological blockade were studied by using two chemically unrelated TRPA1 antagonists: the highly potent and selective compound A967079, which had been characterized earlier, and the relatively new compound 43 ((4R)-1,2,3,4-tetrahydro-4-[3-(3-methoxypropoxy)phenyl]-2-thioxo-5H-indeno[1,2-d]pyrimidin-5-one), which we further characterized in the present study and found to be highly potent (IC50 against cold of â¼8 nm) and selective. Intragastric administration of either antagonist at 30 mg/kg before severe (3°C) cold exposure did not affect the thermoregulatory responses (deep body and tail skin temperatures) of rats, even though plasma concentrations of both antagonists well exceeded their IC50 value at the end of the experiment. In the same experimental setup, blocking the melastatin-8 (TRPM8) channel with AMG2850 (30 mg/kg) attenuated cold-defense mechanisms and led to hypothermia. We conclude that TRPA1 channels do not drive autonomic thermoregulatory responses to cold in rodents.
Subject(s)
Autonomic Nervous System/physiology , Body Temperature Regulation/genetics , Intracellular Signaling Peptides and Proteins/physiology , Thermosensing/genetics , Animals , Body Temperature Regulation/drug effects , CHO Cells , Cold Temperature , Cricetulus , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , HSP90 Heat-Shock Proteins , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/genetics , Male , Mice , Mice, Transgenic , Oximes/blood , Oximes/pharmacology , Pain/chemically induced , Pain/drug therapy , Rats , Rats, Sprague-Dawley , Rats, Wistar , Skin Temperature/drug effects , TRPM Cation Channels/antagonists & inhibitors , Thermosensing/drug effectsABSTRACT
The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.
Subject(s)
Body Temperature/drug effects , TRPV Cation Channels/antagonists & inhibitors , Analgesics/pharmacology , Animals , Calcitonin Gene-Related Peptide/metabolism , Calcium/metabolism , Capsaicin/pharmacology , Cell Line, Transformed , Fever/drug therapy , Fever/physiopathology , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C3H , Neurons/drug effects , Neurons/metabolism , Pain/drug therapy , Pain/metabolism , Pain/physiopathology , Protons , Rats , Rats, Sprague-Dawley , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , TRPV Cation Channels/metabolismSubject(s)
Benzimidazoles/pharmacology , Benzothiazoles/pharmacology , Indazoles/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , TRPV Cation Channels/antagonists & inhibitors , Urea/analogs & derivatives , Analgesics, Non-Narcotic/chemistry , Analgesics, Non-Narcotic/pharmacology , Analgesics, Non-Narcotic/therapeutic use , Benzothiazoles/therapeutic use , Body Temperature Regulation/drug effects , Humans , Pyrimidines/therapeutic use , Urea/pharmacologyABSTRACT
Capsaicin is an agonist of transient receptor potential vanilloid type 1 (TRPV1), in which it can act as a neuronal stimulant and result in nociception. Capsaicin also affects a variety of nonneuronal tissues, in which its mechanisms of action are less certain. The present study investigated whether the inhibitory effects of capsaicin on platelet aggregation are mediated via TRPV1. Venous whole blood obtained from beagle dogs (n = 6) was preincubated with capsaicin and/or the potent and selective competitive TRPV1 antagonist, A-993610 and then exposed to collagen (2 µg/ml). An aggregometer was used to quantify the platelet response. Capsaicin exposure inhibited collagen-induced platelet aggregation in a concentration-dependent manner, with significant effects at 10 and 30 µg capsaicin per millilitre. A-993610 alone (0.1-1.0 µg/ml) had no effects on collagen-induced platelet aggregation, nor did it have any effects on capsaicin's ability to inhibit platelet aggregation. The current results agree with previous findings that capsaicin can inhibit platelet aggregation. In addition, the present study demonstrates that capsaicin's inhibitory effect on collagen-induced canine platelet aggregation is not mediated by TRPV1.
Subject(s)
Capsaicin/pharmacology , Platelet Aggregation/drug effects , TRPV Cation Channels/metabolism , Animals , Dogs , Male , TRPV Cation Channels/agonists , TRPV Cation Channels/antagonists & inhibitorsABSTRACT
Despite the increasing interest in TRPA1 channel as a pain target, its role in cold sensation and body temperature regulation is not clear; the efficacy and particularly side effects resulting from channel blockade remain poorly understood. Here we use a potent, selective, and bioavailable antagonist to address these issues. A-967079 potently blocks human (IC(50): 51 nmol/L, electrophysiology, 67 nmol/L, Ca(2+) assay) and rat TRPA1 (IC(50): 101 nmol/L, electrophysiology, 289 nmol/L, Ca(2+) assay). It is >1000-fold selective over other TRP channels, and is >150-fold selective over 75 other ion channels, enzymes, and G-protein-coupled receptors. Oral dosing of A-967079 produces robust drug exposure in rodents, and exhibits analgesic efficacy in allyl isothiocyanate-induced nocifensive response and osteoarthritic pain in rats (ED(50): 23.2 mg/kg, p.o.). A-967079 attenuates cold allodynia produced by nerve injury but does not alter noxious cold sensation in naive animals, suggesting distinct roles of TRPA1 in physiological and pathological states. Unlike TRPV1 antagonists, A-967079 does not alter body temperature. It also does not produce locomotor or cardiovascular side effects. Collectively, these data provide novel insights into TRPA1 function and suggest that the selective TRPA1 blockade may present a viable strategy for alleviating pain without untoward side effects.
Subject(s)
Body Temperature Regulation/drug effects , Calcium Channels/metabolism , Cold Temperature/adverse effects , Hyperalgesia/drug therapy , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Pain/physiopathology , Sensation/physiology , Transient Receptor Potential Channels/antagonists & inhibitors , Transient Receptor Potential Channels/metabolism , Animals , Blood Pressure/drug effects , Blood Pressure/physiology , Body Temperature/drug effects , Body Temperature/physiology , Body Temperature Regulation/genetics , Body Temperature Regulation/physiology , Calcitonin Gene-Related Peptide/metabolism , Calcium/metabolism , Calcium Channels/genetics , Cells, Cultured , Disease Models, Animal , Drug Interactions , Ganglia, Spinal/pathology , Heart Rate/drug effects , Heart Rate/physiology , Humans , Hyperalgesia/physiopathology , Inhibitory Concentration 50 , Isothiocyanates/pharmacology , Magnetic Resonance Imaging/methods , Male , Mice , Nerve Tissue Proteins/genetics , Neurons/drug effects , Oximes/pharmacology , Oximes/therapeutic use , Pain/drug therapy , Pain/genetics , Pain/metabolism , Pain Measurement/methods , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Sensation/drug effects , Sensory Thresholds/drug effects , TRPA1 Cation Channel , TRPV Cation Channels/genetics , TRPV Cation Channels/metabolism , Transient Receptor Potential Channels/genetics , TritiumABSTRACT
An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel.
Subject(s)
Heterocyclic Compounds/chemical synthesis , Oxazoles/chemical synthesis , Quinolines/chemical synthesis , TRPV Cation Channels/antagonists & inhibitors , Thiourea/chemical synthesis , Capsaicin/chemistry , Crystallography, X-Ray , Heterocyclic Compounds/chemistry , Magnetic Resonance Spectroscopy , Molecular Structure , Oxazoles/chemistry , Quinolines/chemistry , Structure-Activity Relationship , TRPV Cation Channels/chemistry , Thiourea/chemistryABSTRACT
Na(v)1.8 (also known as PN3) is a tetrodotoxin-resistant (TTx-r) voltage-gated sodium channel (VGSC) that is highly expressed on small diameter sensory neurons. It has been implicated in the pathophysiology of inflammatory and neuropathic pain, and we envisioned that selective blockade of Na(v)1.8 would be analgesic, while reducing adverse events typically associated with non-selective VGSC blocking therapeutic agents. Herein, we describe the preparation and characterization of a series of 6-aryl-2-pyrazinecarboxamides, which are potent blockers of the human Na(v)1.8 channel and also block TTx-r sodium currents in rat dorsal root ganglia (DRG) neurons. Selected derivatives display selectivity versus human Na(v)1.2. We further demonstrate that an example from this series is orally bioavailable and produces antinociceptive activity in vivo in a rodent model of neuropathic pain following oral administration.
Subject(s)
Neuralgia/drug therapy , Pyrazines/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/chemistry , Administration, Oral , Animals , Disease Models, Animal , Drug Evaluation, Preclinical , Ganglia, Spinal/cytology , Humans , Microsomes/metabolism , NAV1.8 Voltage-Gated Sodium Channel , Neurons/metabolism , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channel Blockers/therapeutic use , Sodium Channels/metabolism , Structure-Activity RelationshipABSTRACT
A series of aryl-substituted nicotinamide derivatives with selective inhibitory activity against the Na(v)1.8 sodium channel is reported. Replacement of the furan nucleus and homologation of the anilide linker in subtype-selective blocker A-803467 (1) provided potent, selective derivatives with improved aqueous solubility and oral bioavailability. Representative compounds from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Subject(s)
Niacinamide/pharmacology , Sodium Channel Blockers/pharmacology , Administration, Oral , Animals , Biological Availability , Niacinamide/chemistry , Niacinamide/pharmacokinetics , Rats , Sodium Channel Blockers/administration & dosage , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacokinetics , Structure-Activity RelationshipABSTRACT
IMPORTANCE OF THE FIELD: Transient receptor potential vanilloid-1 (TRPV1, vanilloid receptor-1) is a nonspecific cation channel that can be activated by multiple endogenous stimuli and by capsaicin, the active ingredient in chili peppers. TRPV1 is expressed predominantly on sensory neurons where it is proposed to serve as a key nodal point in pain transmission pathways. Pharmacological blockade of TRPV1 represents a compelling strategy for the treatment of a variety of disease states, particularly those requiring chronic pain management. AREA COVERED IN THE REVIEW: This review summarizes patent literature and progress in defining the utility of small molecule TRPV1 antagonists during 2008-2009. WHAT THE READER WILL GAIN: Representative compounds and key characterization data comprising multiple chemical series are highlighted. TAKE HOME MESSAGE: The continued profusion of reports, in both the primary and patent literature, attests to the sustained interest in the TRPV1 class of therapeutics. Although a number of compounds have now been brought forward for human clinical trials, the therapeutic utility of TRPV1 antagonists is yet to be validated unequivocally.
Subject(s)
Drug Design , Pain/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Analgesics/pharmacology , Animals , Chronic Disease , Clinical Trials as Topic , Humans , Pain/physiopathology , Patents as TopicABSTRACT
The TRPV1 antagonist A-995662 demonstrates analgesic efficacy in monoiodoacetate-induced osteoarthritic (OA) pain in rat, and repeated dosing results in increased in vivo potency and a prolonged duration of action. To identify possible mechanism(s) underlying these observations, release of neuropeptides and the neurotransmitter glutamate from isolated spinal cord was measured. In OA rats, basal release of glutamate, bradykinin and calcitonin gene-related peptide (CGRP) was significantly elevated compared to naïve levels, whereas substance P (SP) levels were not changed. In vitro studies showed that capsaicin-evoked TRPV1-dependent CGRP release was 54.7+/-7.7% higher in OA, relative to levels measured for naïve rats, suggesting that TRPV1 activity was higher under OA conditions. The efficacy of A-995662 in OA corresponded with its ability to inhibit glutamate and CGRP release from the spinal cord. A single, fully efficacious dose of A-995662, 100 micromol/kg, reduced spinal glutamate and CGRP release, while a single sub-efficacious dose of A-995662 (25 micromol/kg) was ineffective. Multiple dosing with A-995662 increased the potency and duration of efficacy in OA rats. Changes in efficacy did not correlate with plasma concentrations of A-995662, but were accompanied with reductions in spinal glutamate release. These findings suggest that repeated dosing of TRPV1 antagonists enhances therapeutic potency and duration of action against OA pain, at least in part, by the sustained reduction in release of glutamate and CGRP from the spinal cord.