RESUMO
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.
Assuntos
Anti-Hipertensivos/farmacologia , Citocromo P-450 CYP11B2/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Indazóis/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Inibidores da Aromatase/síntese química , Inibidores da Aromatase/farmacocinética , Inibidores da Aromatase/farmacologia , Linhagem Celular , Cricetulus , Inibidores do Citocromo P-450 CYP2D6/síntese química , Inibidores do Citocromo P-450 CYP2D6/farmacocinética , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Humanos , Indazóis/síntese química , Indazóis/farmacocinética , Macaca mulatta , Masculino , Ratos Sprague-Dawley , Estereoisomerismo , Esteroide 11-beta-Hidroxilase/antagonistas & inibidoresRESUMO
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.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Propionatos/química , Propionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Benzofuranos/sangue , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ensaios de Triagem em Larga Escala , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Camundongos , Propionatos/sangue , Receptores Acoplados a Proteínas G/metabolismoRESUMO
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.
Assuntos
Benzazepinas/farmacologia , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Modelos Animais de Doenças , RatosRESUMO
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.
Assuntos
Bloqueadores dos Canais de Cálcio/química , Canais de Cálcio Tipo N/efeitos dos fármacos , Indóis/química , Triazóis/química , Bloqueadores dos Canais de Cálcio/farmacologia , Linhagem Celular , Humanos , Indóis/farmacologia , Concentração Inibidora 50 , Potenciais da Membrana/efeitos dos fármacos , Técnicas de Patch-Clamp , Triazóis/farmacologiaRESUMO
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.
Assuntos
Analgésicos/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/fisiologia , Indóis/farmacologia , Triazóis/farmacologia , Analgésicos/efeitos adversos , Analgésicos/farmacocinética , Animais , Barorreflexo/efeitos dos fármacos , Disponibilidade Biológica , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo N/genética , Canais de Cálcio Tipo R/fisiologia , Proteínas de Transporte de Cátions/fisiologia , Linhagem Celular , Cães , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/fisiologia , Hiperalgesia/tratamento farmacológico , Hipotensão Ortostática/induzido quimicamente , Indóis/efeitos adversos , Indóis/farmacocinética , Masculino , Camundongos , Camundongos Knockout , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Dor/tratamento farmacológico , Dor/etiologia , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Triazóis/efeitos adversos , Triazóis/farmacocinéticaRESUMO
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.
Assuntos
Anticonvulsivantes/farmacologia , Benzodiazepinonas/farmacologia , Epilepsia/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntese química , Benzodiazepinonas/farmacocinética , Eletrofisiologia , Eletrochoque , Epilepsia/metabolismo , Canais de Potássio Éter-A-Go-Go/metabolismo , Transferência Ressonante de Energia de Fluorescência , Humanos , Camundongos , Estrutura Molecular , Ratos , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/farmacocinéticaRESUMO
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.
Assuntos
Piridinas/química , Piridinas/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Analgésicos/química , Analgésicos/farmacologia , Animais , Inflamação/tratamento farmacológico , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Dor/tratamento farmacológico , Ratos , Bloqueadores dos Canais de Sódio/farmacocinética , Relação Estrutura-AtividadeRESUMO
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.
RESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Isoquinolinas/química , Isoquinolinas/farmacologia , Triglicerídeos/metabolismo , Animais , Diacilglicerol O-Aciltransferase/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/administração & dosagem , Isoquinolinas/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Triglicerídeos/sangueRESUMO
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.
RESUMO
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.
Assuntos
Benzazepinas/química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/fisiologia , Animais , Benzazepinas/metabolismo , Benzazepinas/farmacologia , Ligação Competitiva , Linhagem Celular , Membrana Celular/metabolismo , Eletrofisiologia , Humanos , Potenciais da Membrana/efeitos dos fármacos , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Canal de Sódio Disparado por Voltagem NAV1.8 , Ensaio Radioligante , Ratos , Bloqueadores dos Canais de Sódio/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/efeitos dos fármacos , Canais de Sódio/metabolismo , Sinaptossomos/metabolismoRESUMO
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.
Assuntos
Benzodiazepinonas/síntese química , Benzodiazepinonas/uso terapêutico , Neuralgia/tratamento farmacológico , Bloqueadores dos Canais de Sódio/síntese química , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/efeitos dos fármacos , Animais , Benzodiazepinonas/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Ratos , Bloqueadores dos Canais de Sódio/farmacocinética , Canais de Sódio/químicaRESUMO
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.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/classificação , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Animais , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacologia , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Ratos , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/uso terapêutico , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Receptores de Serotonina/química , Receptores de Serotonina/metabolismo , Sulfonas/química , Sulfonas/metabolismo , Alquilação , Aminação , Ciclização , Ligantes , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonas/síntese químicaRESUMO
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.
Assuntos
Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Animais , Células CHO , Cricetinae , Ciclização , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HumanosRESUMO
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.