ABSTRACT
The Biological and Medicinal Chemistry Sector (BMCS) is an important interest group within the UK's Royal Society of Chemistry (RSC). Operating through a committee of voluntary members, the main goal of the BMCS is to share knowledge within the sector, primarily by organizing high quality scientific meetings, with a particular focus on networking. Financial support and tailored scientific programmes encourage training and development across multiple generations, from school age through to retirement. Scientific excellence is recognised through several high-profile awards.
Subject(s)
Chemistry, Pharmaceutical , Humans , Societies, Scientific , United KingdomABSTRACT
Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.
ABSTRACT
Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Carbamazepine/pharmacology , Phenyl Ethers/pharmacokinetics , Proline/analogs & derivatives , Voltage-Gated Sodium Channel Blockers/pharmacokinetics , Adult , Analgesics, Non-Narcotic/adverse effects , Analgesics, Non-Narcotic/pharmacokinetics , Carbamazepine/adverse effects , Carbamazepine/pharmacokinetics , Double-Blind Method , Drug Interactions , Drug Therapy, Combination , Female , Healthy Volunteers , Humans , Male , NAV1.7 Voltage-Gated Sodium Channel , Phenyl Ethers/adverse effects , Phenyl Ethers/blood , Phenyl Ethers/pharmacology , Proline/adverse effects , Proline/blood , Proline/pharmacokinetics , Proline/pharmacology , Voltage-Gated Sodium Channel Blockers/adverse effects , Voltage-Gated Sodium Channel Blockers/blood , Young AdultABSTRACT
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Subject(s)
Anti-Inflammatory Agents/chemistry , Isoindoles/chemistry , Receptors, Prostaglandin E, EP4 Subtype/agonists , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/therapeutic use , Blood Cells/cytology , Blood Cells/drug effects , Blood Cells/metabolism , Dinoprostone/chemistry , Dinoprostone/therapeutic use , Drug Evaluation, Preclinical , Half-Life , Humans , Inhibitory Concentration 50 , Isoindoles/pharmacokinetics , Isoindoles/therapeutic use , Lipopolysaccharides/pharmacology , Pain/drug therapy , Pain/pathology , Pain/veterinary , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Rats , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Trigeminal neuralgia (TN) is a rare severe unilateral facial pain condition. Current guidelines in trigeminal neuralgia management recommend sodium channel blockers--carbamazepine or oxcarbazepine--as the first-line treatment. However, the currently available drugs are often associated with poor tolerability resulting in sub-optimal pain control. CNV1014802 is a novel sodium channel blocker that is being assessed in the treatment of trigeminal neuralgia. Due to the severity of the condition, it is not ethical to conduct a traditional placebo-controlled randomized controlled trial. It is also difficult to use an active control such as carbamazepine, the current gold standard, because of its complex pharmacology and potential for drug interactions. METHODS/DESIGN: The trial uses a randomized withdrawal design to assess efficacy in this rare condition. There is a 21-day open-label phase followed by a randomized 28-day placebo-controlled phase for responders. Thirty patients will be randomized. The primary outcome measure will be pain relief, but secondary measures of quality of life will be of significant importance given the effect of this condition on activities of daily living. Safety and adverse event endpoints are described. DISCUSSION: There have been very few well-controlled, randomized, placebo-controlled studies in trigeminal neuralgia, and the majority of drugs have had other primary uses. Due to the severity of the pain, minimizing the time a patient is administered placebo was a key factor in designing this study. This study will not only provide data on the efficacy of CNV1014802 in trigeminal neuralgia, but will also provide information on the effectiveness and acceptability of a novel trial design in trigeminal neuralgia. TRIAL REGISTRATION: Trial number NCT01540630.
Subject(s)
Phenyl Ethers/therapeutic use , Proline/analogs & derivatives , Research Design , Sodium Channel Blockers/therapeutic use , Trigeminal Neuralgia/drug therapy , Double-Blind Method , Humans , Outcome Assessment, Health Care , Phenyl Ethers/adverse effects , Proline/adverse effects , Proline/therapeutic use , Sodium Channel Blockers/adverse effects , Withholding TreatmentABSTRACT
The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor, thought to play a role in energy metabolism, glucose homeostasis and microglia-mediated neuroinflammation. A novel benzimidazole series of centrally penetrant PPARγ partial agonists has been identified. The optimization of PPARγ activity and in vivo pharmacokinetics leading to the identification of GSK1997132B a potent, metabolically stable and centrally penetrant PPARγ partial agonist, is described.
Subject(s)
Benzimidazoles/pharmacology , Drug Discovery , PPAR gamma/antagonists & inhibitors , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Dose-Response Relationship, Drug , Molecular Structure , PPAR gamma/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Benzofurans/chemistry , Receptors, Prostaglandin E, EP1 Subtype/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzofurans/pharmacokinetics , Benzofurans/therapeutic use , Cell Line , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Pain/drug therapy , Rats , Receptors, Prostaglandin E, EP1 Subtype/metabolism , Structure-Activity RelationshipABSTRACT
BACKGROUND: Cleavage of the amyloid precursor protein (APP) by ß-site APP-cleaving enzyme and γ-secretase results in the generation of amyloid-ß (Aß) peptides that aggregate and deposit as senile plaques in brains of Alzheimer disease patients. Due to the fundamental role γ-secretase plays in the proteolysis of a number of proteins including Notch, pharmacological inhibition of γ-secretase has been associated with mechanism-based toxicities. Therefore, efforts have focussed on the modulation of γ-secretase activity to selectively decrease levels of Aß42 peptide while avoiding deleterious activity on Notch processing. OBJECTIVE: Here, we describe the in vitro and in vivo characterisation of a novel γ-secretase modulator, GSM-10h, and investigate the potential for shorter Aß peptides to induce neurotoxicity in rat primary cortical neurons. METHODS: The effect of GSM-10h on Aß levels was investigated in SH-SY5Y cells expressing mutant APP and in TASTPM mice expressing APP and presenilin-1 mutant transgenes. The effect of GSM-10h on Notch processing was also determined. RESULTS: In cells, GSM-10h decreased levels of Aß42 while concomitantly increasing levels of Aß38 in the absence of effects on Aß40 levels. In TASTPM mice, GSM-10h effectively lowered brain Aß42 and increased brain Aß38, with no effect on Notch signalling. Unlike Aß42, which causes neuronal cell death, neither Aß37 nor Aß38 were neurotoxic. CONCLUSIONS: These findings confirm GSM-10h exhibits the profile of a γ-secretase modulator. In addition, TASTPM mice are shown to be responsive to treatment with a γ-secretase modulator, thereby highlighting the utility of this bitransgenic mouse model in drug discovery efforts focussed on the development of γ-secretase modulators.
Subject(s)
Acetates/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Protein Precursor/biosynthesis , Peptide Fragments/antagonists & inhibitors , Piperidines/pharmacology , Presenilin-1/biosynthesis , Amyloid beta-Protein Precursor/genetics , Animals , Cell Death/drug effects , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/pathology , Presenilin-1/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Transgenes/geneticsABSTRACT
This Letter details the SAR of a novel series of piperidine-derived gamma-secretase modulators. Compound 10h was found to be a potent modulator in vitro, which on further profiling, was found to decrease Abeta42, increase Abeta38 and have no effect on Abeta40 levels. Furthermore, 10h demonstrated excellent pharmacokinetic parameters in the mouse, rat and dog in addition to good CNS penetration in the mouse.
Subject(s)
Acetates/chemistry , Amyloid Precursor Protein Secretases/physiology , Piperidines/chemistry , Acetates/metabolism , Acetates/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Amyloid beta-Peptides/metabolism , Animals , Cell Line, Tumor , Dogs , Humans , Mice , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/biosynthesis , Peptide Fragments/metabolism , Piperidines/metabolism , Piperidines/pharmacology , Rats , Structure-Activity Relationship , Substrate Specificity/drug effectsABSTRACT
A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.
Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Isoquinolines/chemical synthesis , Pyridazines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacokinetics , Isoquinolines/chemistry , Isoquinolines/pharmacokinetics , Pain/drug therapy , Pyridazines/chemistry , Pyridazines/pharmacokinetics , Rats , Receptor, Cannabinoid, CB2/metabolism , Structure-Activity RelationshipABSTRACT
2-Amino-5-aryl-pyridines, exemplified by compound 1, had been identified as a synthetically tractable series of CB(2) agonists from a high-throughput screen of the GlaxoSmithKline compound collection. Described herein are the results of an investigation of the structure-activity relationships (SAR) which led to the identification a number of potent and selective agonists.
Subject(s)
Pyridines/chemical synthesis , Pyridines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Drug Design , Molecular Structure , Pyridines/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
Subject(s)
Aminopyridines/therapeutic use , Brain/metabolism , Morpholines/therapeutic use , Pain/drug therapy , Receptor, Cannabinoid, CB2/agonists , Aminopyridines/pharmacokinetics , Animals , Aza Compounds , CHO Cells , Cell Line , Chronic Disease , Cricetinae , Cricetulus , Drug Discovery , Humans , Indoles , Morpholines/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
We describe the medicinal chemistry programme that led to the identification of the EP(1) receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP(1) antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
Subject(s)
Analgesics/chemical synthesis , Chemistry, Pharmaceutical/methods , Inflammation/drug therapy , Nicotinic Acids/chemical synthesis , Pyridines/chemical synthesis , Receptors, Prostaglandin E/antagonists & inhibitors , Analgesics/pharmacology , Animals , Central Nervous System/drug effects , Drug Design , Humans , Hydrogen-Ion Concentration , Inhibitory Concentration 50 , Models, Chemical , Nicotinic Acids/pharmacology , Pyridines/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.
Subject(s)
Inflammation/drug therapy , Pain/drug therapy , Pyridines/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Animals , Drug Evaluation, Preclinical , Pyridines/chemistry , Pyridines/therapeutic use , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Subject(s)
Analgesics/chemical synthesis , Pyridines/chemical synthesis , Pyridines/therapeutic use , Receptor, Cannabinoid, CB2/agonists , Amides/chemical synthesis , Amides/pharmacology , Amides/therapeutic use , Analgesia/methods , Animals , Disease Models, Animal , Drug Discovery/methods , Inflammation , Pain/drug therapy , Pyridines/pharmacology , Structure-Activity RelationshipABSTRACT
We describe the discovery of a series of pyrazole amide EP(1) receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1-2.0:1 in addition to good solubility and metabolic stability.
Subject(s)
Brain/drug effects , Central Nervous System/drug effects , Pyrazoles/chemistry , Receptors, Prostaglandin E/antagonists & inhibitors , Amides/chemistry , Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Isoquinolines/chemistry , Models, Chemical , Molecular Structure , Receptors, Prostaglandin E, EP1 Subtype , Solubility , Structure-Activity RelationshipABSTRACT
Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP(1) receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Pyrazoles/chemical synthesis , Pyrazoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Analgesics/chemistry , Animals , Brain/drug effects , Central Nervous System/drug effects , Combinatorial Chemistry Techniques , Disease Models, Animal , Dose-Response Relationship, Drug , Molecular Structure , Pain Measurement , Pyrazoles/chemistry , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
We describe the medicinal chemistry approach that generated a novel indole series of EP(1) receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Receptors, Prostaglandin E/metabolism , Animals , Humans , Hydrogen Bonding , Indoles/chemistry , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Rats , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
We describe the SAR, in terms of heterocyclic replacements, for a series of pyrazole EP(1) receptor antagonists. This study led to the identification of several aromatic heterocyclic replacements for the pyrazole in the original compound. Investigation of replacements for the methylene linker uncovered disparate SAR in the thiazole and pyridine series.
Subject(s)
Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Models, Molecular , Molecular Structure , Protein Binding , Receptors, Prostaglandin E, EP1 Subtype , Structure-Activity RelationshipABSTRACT
This review summarizes the publication and patent literature reporting on prostaglandin E(2) receptor 1 (EP(1)) antagonists from 2006 to the present. Pertinent references from 2005 are also included. New chemical entities disclosed as EP(1) antagonists are highlighted with particular focus on their potential to treat inflammatory pain. In the time period covered by this review there has been a significant increase in the number of publications describing EP(1) antagonists. Several papers detail in vivo efficacy in preclinical models of inflammatory pain and overactive bladder. It is evident that at least one molecule, if not more, has been selected as a development candidate. In addition to acidic antagonists, several research groups have detailed their efforts to identify non-acidic EP(1) antagonists. Progress in this challenging area is evident from the excellent in vitro activity that has been described to date.