ABSTRACT
We report the discovery and hit-to-lead optimization of a structurally novel indazole series of CYP11B2 inhibitors. Benchmark compound 34 from this series displays potent inhibition of CYP11B2, high selectivity versus related steroidal and hepatic CYP targets, and lead-like physical and pharmacokinetic properties. On the basis of these and other data, the indazole series was progressed to lead optimization for further refinement.
Subject(s)
Antihypertensive Agents/pharmacology , Cytochrome P-450 CYP11B2/antagonists & inhibitors , Hypertension/drug therapy , Indazoles/pharmacology , Animals , Antihypertensive Agents/chemical synthesis , Antihypertensive Agents/pharmacokinetics , Aromatase Inhibitors/chemical synthesis , Aromatase Inhibitors/pharmacokinetics , Aromatase Inhibitors/pharmacology , Cell Line , Cricetulus , Cytochrome P-450 CYP2D6 Inhibitors/chemical synthesis , Cytochrome P-450 CYP2D6 Inhibitors/pharmacokinetics , Cytochrome P-450 CYP2D6 Inhibitors/pharmacology , Humans , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Macaca mulatta , Male , Rats, Sprague-Dawley , Stereoisomerism , Steroid 11-beta-Hydroxylase/antagonists & inhibitorsABSTRACT
Type 2 diabetes mellitus (T2DM) is an ever increasing worldwide epidemic, and the identification of safe and effective insulin sensitizers, absent of weight gain, has been a long-standing goal of diabetes research. G-protein coupled receptor 120 (GPR120) has recently emerged as a potential therapeutic target for treating T2DM. Natural occurring, and more recently, synthetic agonists have been associated with insulin sensitizing, anti-inflammatory, and fat metabolism effects. Herein we describe the design, synthesis, and evaluation of a novel spirocyclic GPR120 agonist series, which culminated in the discovery of potent and selective agonist 14. Furthermore, compound 14 was evaluated in vivo and demonstrated acute glucose lowering in an oral glucose tolerance test (oGTT), as well as improvements in homeostatic measurement assessment of insulin resistance (HOMA-IR; a surrogate marker for insulin sensitization) and an increase in glucose infusion rate (GIR) during a hyperinsulinemic euglycemic clamp in diet-induced obese (DIO) mice.
ABSTRACT
Herein we report the discovery and hit-to-lead optimization of a series of spirocyclic piperidine aldosterone synthase (CYP11B2) inhibitors. Compounds from this series display potent CYP11B2 inhibition, good selectivity versus related CYP enzymes, and lead-like physical and pharmacokinetic properties.
ABSTRACT
The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the "left-hand" aryl group led to compound 6, which demonstrated a GPR120 mechanism-based pharmacodynamic effect in a mouse oral glucose tolerance test (oGTT). Further optimization gave rise to the benzofuran propanoic acid series (exemplified by compound 37), which demonstrated acute mechanism-based pharmacodynamic effects. The combination of in vivo efficacy and attractive rodent pharmacodynamic profiles suggests compounds generated from this series may afford attractive candidates for the treatment of Type 2 diabetes.
Subject(s)
Benzofurans/chemistry , Benzofurans/pharmacology , Propionates/chemistry , Propionates/pharmacology , Receptors, G-Protein-Coupled/agonists , Animals , Benzofurans/blood , Blood Glucose/analysis , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Hypoglycemic Agents/blood , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Mice , Propionates/blood , Receptors, G-Protein-Coupled/metabolismABSTRACT
DGAT2 plays a critical role in hepatic triglyceride production, and data suggests that inhibition of DGAT2 could prove to be beneficial in treating a number of disease states. This article documents the discovery and optimization of a selective small molecule inhibitor of DGAT2 as well as pharmacological proof of biology in a mouse model of triglyceride production.
Subject(s)
Diacylglycerol O-Acyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Isoquinolines/chemistry , Isoquinolines/pharmacology , Triglycerides/metabolism , Animals , Diacylglycerol O-Acyltransferase/metabolism , Drug Discovery , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Humans , Isoquinolines/administration & dosage , Isoquinolines/pharmacokinetics , Male , Mice , Mice, Inbred C57BL , Triglycerides/bloodABSTRACT
Hit-to-lead efforts resulted in the discovery of compound 19, a potent CYP11B2 inhibitor that displays high selectivity vs related CYPs, good pharmacokinetic properties in rat and rhesus, and lead-like physical properties. In a rhesus pharmacodynamic model, compound 19 displays robust, dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
ABSTRACT
We report the discovery of a benzimidazole series of CYP11B2 inhibitors. Hit-to-lead and lead optimization studies identified compounds such as 32, which displays potent CYP11B2 inhibition, high selectivity versus related CYP targets, and good pharmacokinetic properties in rat and rhesus. In a rhesus pharmacodynamic model, 32 produces dose-dependent aldosterone lowering efficacy, with no apparent effect on cortisol levels.
ABSTRACT
A series of benzazepinones were synthesized and evaluated for block of Nav1.7 sodium channels. Compound 30 from this series displayed potent channel block, good selectivity versus other targets, and dose-dependent oral efficacy in a rat model of neuropathic pain.
Subject(s)
Benzazepines/pharmacology , Neuralgia/drug therapy , Sodium Channel Blockers/pharmacology , Animals , Disease Models, Animal , RatsABSTRACT
Biological, genetic, and clinical evidence provide validation for N-type calcium channels (Ca(V)2.2) as therapeutic targets for chronic pain. A state-dependent Ca(V)2.2 inhibitor may provide an improved therapeutic window over ziconotide, the peptidyl Ca(V)2.2 inhibitor used clinically. Supporting this notion, we recently reported that in preclinical models, the state-dependent Ca(V)2 inhibitor (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1) has an improved therapeutic window compared with ziconotide. Here we characterize TROX-1 inhibition of Cav2.2 channels in more detail. When channels are biased toward open/inactivated states by depolarizing the membrane potential under voltage-clamp electrophysiology, TROX-1 inhibits Ca(V)2.2 channels with an IC(50) of 0.11 µM. The voltage dependence of Ca(V)2.2 inhibition was examined using automated electrophysiology. TROX-1 IC(50) values were 4.2, 0.90, and 0.36 µM at -110, -90, and -70 mV, respectively. TROX-1 displayed use-dependent inhibition of Ca(V)2.2 with a 10-fold IC(50) separation between first (27 µM) and last (2.7 µM) pulses in a train. In a fluorescence-based calcium influx assay, TROX-1 inhibited Ca(V)2.2 channels with an IC(50) of 9.5 µM under hyperpolarized conditions and 0.69 µM under depolarized conditions. Finally, TROX-1 potency was examined across the Ca(V)2 subfamily. Depolarized IC(50) values were 0.29, 0.19, and 0.28 µM by manual electrophysiology using matched conditions and 1.8, 0.69, and 1.1 µM by calcium influx for Ca(V)2.1, Ca(V)2.2, and Ca(V)2.3, respectively. Together, these in vitro data support the idea that a state-dependent, non-subtype-selective Ca(V)2 channel inhibitor can achieve an improved therapeutic window over the relatively state-independent Ca(V)2.2-selective inhibitor ziconotide in preclinical models of chronic pain.
Subject(s)
Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/drug effects , Indoles/chemistry , Triazoles/chemistry , Calcium Channel Blockers/pharmacology , Cell Line , Humans , Indoles/pharmacology , Inhibitory Concentration 50 , Membrane Potentials/drug effects , Patch-Clamp Techniques , Triazoles/pharmacologyABSTRACT
Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50) > 20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.
Subject(s)
Analgesics/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/physiology , Indoles/pharmacology , Triazoles/pharmacology , Analgesics/adverse effects , Analgesics/pharmacokinetics , Animals , Baroreflex/drug effects , Biological Availability , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, N-Type/genetics , Calcium Channels, R-Type/physiology , Cation Transport Proteins/physiology , Cell Line , Dogs , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Hyperalgesia/drug therapy , Hypotension, Orthostatic/chemically induced , Indoles/adverse effects , Indoles/pharmacokinetics , Male , Mice , Mice, Knockout , Neurons/drug effects , Neurons/physiology , Pain/drug therapy , Pain/etiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Triazoles/adverse effects , Triazoles/pharmacokineticsABSTRACT
A series of imidazopyridines were evaluated as potential sodium channel blockers for the treatment of neuropathic pain. Several members were identified with good hNa(v)1.7 potency and excellent rat pharmacokinetic profiles. Compound 4 had good efficacy (52% and 41% reversal of allodynia at 2 and 4h post-dose, respectively) in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain when dosed orally at 10mg/kg.
Subject(s)
Pyridines/chemistry , Pyridines/pharmacology , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Analgesics/chemistry , Analgesics/pharmacology , Animals , Inflammation/drug therapy , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel , Pain/drug therapy , Rats , Sodium Channel Blockers/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Subject(s)
Anticonvulsants/pharmacology , Benzodiazepinones/pharmacology , Epilepsy/drug therapy , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Sodium Channel Blockers/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacokinetics , Benzodiazepinones/chemical synthesis , Benzodiazepinones/pharmacokinetics , Electrophysiology , Electroshock , Epilepsy/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Fluorescence Resonance Energy Transfer , Humans , Mice , Molecular Structure , Rats , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacokineticsABSTRACT
Voltage-gated sodium channels (Nav1) transmit pain signals from peripheral nociceptive neurons, and blockers of these channels have been shown to ameliorate a number of pain conditions. Because these drugs can have adverse effects that limit their efficacy, more potent and selective Nav1 inhibitors are being pursued. Recent human genetic data have provided strong evidence for the involvement of the peripheral nerve sodium channel subtype, Nav1.7, in the signaling of nociceptive information, highlighting the importance of identifying selective Nav1.7 blockers for the treatment of chronic pain. Using a high-throughput functional assay, novel Nav1.7 blockers, namely, the 1-benzazepin-2-one series, have recently been identified. Further characterization of these agents indicates that, in addition to high-affinity inhibition of Nav1.7 channels, selectivity against the Nav1.5 and Nav1.8 subtypes can also be achieved within this structural class. The most potent, nonselective member of this class of Nav1.7 blockers has been radiolabeled with tritium. [3H]BNZA binds with high affinity to rat brain synaptosomal membranes (Kd = 1.5 nM) and to membranes prepared from HEK293 cells stably transfected with hNav1.5 (Kd = 0.97 nM). In addition, and for the first time, high-affinity binding of a radioligand to hNav1.7 channels (Kd = 1.6 nM) was achieved with [3H]BNZA, providing an additional means for identifying selective Nav1.7 channel inhibitors. Taken together, these data suggest that members of the novel 1-benzazepin-2-one structural class of Nav1 blockers can display selectivity toward the peripheral nerve Nav1.7 channel subtype, and with appropriate pharmacokinetic and drug metabolism properties, these compounds could be developed as analgesic agents.
Subject(s)
Benzazepines/chemistry , Sodium Channel Blockers/chemistry , Sodium Channels/physiology , Animals , Benzazepines/metabolism , Benzazepines/pharmacology , Binding, Competitive , Cell Line , Cell Membrane/metabolism , Electrophysiology , Humans , Membrane Potentials/drug effects , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel , NAV1.8 Voltage-Gated Sodium Channel , Radioligand Assay , Rats , Sodium Channel Blockers/metabolism , Sodium Channel Blockers/pharmacology , Sodium Channels/drug effects , Sodium Channels/metabolism , Synaptosomes/metabolismABSTRACT
A series of benzazepinones were synthesized and evaluated as hNa(v)1.7 sodium channel blockers. Several compounds from this series displayed good oral bioavailability and exposure and were efficacious in a rat model of neuropathic pain.
Subject(s)
Benzodiazepinones/chemical synthesis , Benzodiazepinones/therapeutic use , Neuralgia/drug therapy , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/therapeutic use , Sodium Channels/drug effects , Animals , Benzodiazepinones/pharmacokinetics , Biological Availability , Disease Models, Animal , Dogs , Drug Evaluation, Preclinical , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel , Rats , Sodium Channel Blockers/pharmacokinetics , Sodium Channels/chemistryABSTRACT
A series of benzodiazepines and benzazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of the benzazepinone series, compound 47, displayed potent, state-dependent block of hNa(v)1.7, and was orally efficacious in a rat model of neuropathic pain.
Subject(s)
Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/therapeutic use , Pain/drug therapy , Sodium Channel Blockers/classification , Sodium Channel Blockers/pharmacology , Sodium Channels/metabolism , Animals , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/pharmacology , Molecular Structure , NAV1.7 Voltage-Gated Sodium Channel , Rats , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/therapeutic use , Structure-Activity RelationshipABSTRACT
1-Phenyl-8-azabicyclo[3.2.1]octane ethers are NK(1) receptor antagonists. Substitution at the 6-exo-position led to high affinity NK(1) antagonists with a prolonged duration of action in vivo. Incorporation of an alpha-methyl substituent in the pendent benzyl ether side chain gave compounds with increased selectivity over the hERG channel.
Subject(s)
Aza Compounds/pharmacology , Bridged Bicyclo Compounds/pharmacology , Neurokinin-1 Receptor Antagonists , Animals , CHO Cells , Cricetinae , Cyclization , Ether-A-Go-Go Potassium Channels/drug effects , HumansABSTRACT
A novel series of 5-HT(7) receptor ligands has been identified and evaluated, providing compounds showing a broad spectrum of functional activities and good selectivity over selected receptors and ion channels.
Subject(s)
Receptors, Serotonin/chemistry , Receptors, Serotonin/metabolism , Sulfones/chemistry , Sulfones/metabolism , Alkylation , Amination , Cyclization , Ligands , Molecular Structure , Structure-Activity Relationship , Sulfones/chemical synthesisABSTRACT
Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.