RESUMEN
In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 µg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 µg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.
Asunto(s)
Coenzima A/metabolismo , Modelos Animales de Enfermedad , Neurodegeneración Asociada a Pantotenato Quinasa/tratamiento farmacológico , Ácido Pantoténico/análogos & derivados , Profármacos/uso terapéutico , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neurodegeneración Asociada a Pantotenato Quinasa/metabolismo , Ácido Pantoténico/farmacocinética , Ácido Pantoténico/farmacología , Ácido Pantoténico/uso terapéutico , Fosfotransferasas (Aceptor de Grupo Alcohol)/deficiencia , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Profármacos/farmacocinética , Profármacos/farmacología , Interferencia de ARN , Ratas Sprague-Dawley , Especificidad de la EspecieRESUMEN
Novel potent and selective 5,6,5- and 5,5,6-tricyclic pyrrolidine dipeptidyl peptidase IV (DPP-4) inhibitors were identified. Structure-activity relationship (SAR) efforts focused on improving the intrinsic DPP-4 inhibition potency, increasing protease selectivity, and demonstrating clean ion channel and cytochrome P450 profiles while trying to achieve a pharmacokinetic profile suitable for once weekly dosing in humans.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Descubrimiento de Drogas , Pirrolidinas/farmacología , Animales , Cristalografía por Rayos X , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.
Asunto(s)
Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Compuestos Heterocíclicos con 2 Anillos/química , Piranos/química , Sulfonamidas/química , Animales , Sitios de Unión , Dipeptidil Peptidasa 4/química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Perros , Semivida , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Piranos/síntesis química , Piranos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Benzazepinas/farmacología , Neuralgia/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/farmacología , Animales , Modelos Animales de Enfermedad , RatasRESUMEN
We report the investigation of sulfonamide-derived Cav2.2 inhibitors to address drug-metabolism liabilities with this lead class of analgesics. Modification of the benzamide substituent provided improvements in both potency and selectivity. However, we discovered that formation of the persistent 3-(trifluoromethyl)benzenesulfonamide metabolite was an endemic problem in the sulfonamide series and that the replacement of the center aminopiperidine scaffold failed to prevent this metabolic pathway. This issue was eventually addressed by application of a bioisostere strategy. The new gem-dimethyl sulfone series retained Cav2.2 potency without the liability of the circulating sulfonamide metabolite.
RESUMEN
The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/química , Canales de Calcio Tipo N/fisiología , Dolor Crónico/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Piperidinas/farmacología , Sulfonamidas/farmacología , Animales , Bloqueadores de los Canales de Calcio/síntesis química , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo N/metabolismo , Células Cultivadas , Perros , Humanos , Ratones , Ratones Noqueados , Microsomas Hepáticos/efectos de los fármacos , Técnicas de Placa-Clamp , Piperidinas/síntesis química , Piperidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Distribución TisularRESUMEN
Bombesin receptor subtype-3 (BRS-3) is an orphan G-protein coupled receptor belonging to the subfamily of bombesin-like receptors. BRS-3 is implicated in the development of obesity and diabetes. We report here small-molecule agonists that are based on a 4-(alkylamino)pyridine-3-sulfonamide core. We describe the discovery of 2a, which has mid-nanomolar potency, selectivity for human BRS-3 versus the other bombesin-like receptors, and good bioavailability.
Asunto(s)
Piridinas/química , Receptores de Bombesina/agonistas , Sulfonamidas/farmacología , Compuestos de Sulfonilurea/farmacología , Animales , Disponibilidad Biológica , Enlace de Hidrógeno , Masculino , Ratas , Ratas Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacocinética , Compuestos de Sulfonilurea/química , Compuestos de Sulfonilurea/farmacocinéticaRESUMEN
A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
Asunto(s)
Ciclohexanos/síntesis química , Ciclohexanos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Disponibilidad Biológica , Ciclohexanos/farmacocinética , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Semivida , Piperidinas/farmacocinética , RatasRESUMEN
N-type calcium channels (Ca(v)2.2) have been shown to play a critical role in pain. A series of low molecular weight 2-aryl indoles were identified as potent Ca(v)2.2 blockers with good in vitro and in vivo potency.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo N/metabolismo , Indoles/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Perros , Haplorrinos , Humanos , Indoles/farmacocinética , Indoles/farmacología , RatasRESUMEN
A series of novel biphenyl pyrazole dicarboxamides were identified as potential sodium channel blockers for treatment of neuropathic pain. Compound 20 had outstanding efficacy in the Chung rat spinal nerve ligation (SNL) model of neuropathic pain.
Asunto(s)
Compuestos de Bifenilo/química , Neuralgia/tratamiento farmacológico , Pirazoles/química , Bloqueadores de los Canales de Sodio/química , Canales de Sodio/química , Animales , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/uso terapéutico , Perros , Evaluación Preclínica de Medicamentos , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Actividad Motora/efectos de los fármacos , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismoRESUMEN
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.
Asunto(s)
Analgésicos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo N/fisiología , Indoles/farmacología , Triazoles/farmacología , Analgésicos/efectos adversos , Analgésicos/farmacocinética , Animales , Barorreflejo/efectos de los fármacos , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/farmacocinética , Canales de Calcio Tipo N/genética , Canales de Calcio Tipo R/fisiología , Proteínas de Transporte de Catión/fisiología , Línea Celular , Perros , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiología , Hiperalgesia/tratamiento farmacológico , Hipotensión Ortostática/inducido químicamente , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/fisiología , Dolor/tratamiento farmacológico , Dolor/etiología , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Triazoles/efectos adversos , Triazoles/farmacocinéticaRESUMEN
BACKGROUND: Voltage-gated sodium channels (Na(v)1) are expressed in primary sensory neurons where they influence excitability via their role in the generation and propagation of action potentials. Recently, human genetic data have shown that one sodium channel subtype, Na(v)1.7, plays a major role in pain. We performed these studies to characterize the antinociceptive effects of N-[(R)-1-((R)-7-chloro-1-isopropyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-ylcarbamoyl)-2-(2-fluorophenyl)-ethyl]-4-fluoro-2-trifluoromethyl-benzamide (BZP), a non-central nervous system (CNS) penetrant small molecule with high affinity and preferential selectivity for Na(v)1.7 over Na(v)1.8 and Na(v)1.5. METHODS: BZP was evaluated in rat preclinical models of inflammatory and neuropathic pain and compared with standard analgesics. Two models were used: the complete Freund's adjuvant model of inflammatory pain and the spinal nerve ligation model of neuropathic pain. BZP was also evaluated in a motor coordination assay to assess its propensity for CNS side effects. RESULTS: In preclinical models of chronic pain, BZP displayed efficacy comparable with that of leading analgesics. In the complete Freund's adjuvant model, BZP produced reversal of hyperalgesia comparable with nonsteroidal antiinflammatory drugs, and in the spinal nerve ligation model, BZP produced reversal of allodynia comparable with gabapentin and mexiletine. Unlike the CNS penetrant compounds gabapentin and mexiletine, BZP did not induce any impairment of motor coordination. CONCLUSIONS: These data suggest that a peripherally acting sodium channel blocker, preferentially acting through Na(v)1.7, could provide clinical relief of chronic pain without the CNS side effects typical of many existing pain treatments.
Asunto(s)
Benzamidas/farmacología , Inflamación , Canales de Sodio/metabolismo , Analgésicos/farmacología , Animales , Línea Celular , Humanos , Hiperalgesia/patología , Masculino , Canal de Sodio Activado por Voltaje NAV1.7 , Degeneración Nerviosa/patología , Dolor , Ratas , Ratas Sprague-Dawley , Nervios Espinales/patologíaRESUMEN
Analogs of the previously reported voltage gated sodium channel blocker CDA54 were prepared in which one of the amide functions was replaced with aromatic and non-aromatic heterocycles. Replacement of the amide with an aromatic heterocycle resulted in significant loss of sodium channel blocking activity, while non-aromatic heterocycle replacements were well tolerated.
Asunto(s)
Isoxazoles/química , Isoxazoles/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Animales , Isoxazoles/uso terapéutico , Modelos Moleculares , Estructura Molecular , Dolor/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley , Bloqueadores de los Canales de Sodio/uso terapéutico , Nervios Espinales/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of novel isoxazole voltage gated sodium channel blockers have been synthesized and evaluated. Substitutions on the benzylic position of benzamide were investigated to determine their effect on Na(v)1.7 inhibitory potency. The spirocyclobutyl substitution had the most significant enhancement on Na(v)1.7 inhibitory activity.
Asunto(s)
Isoxazoles/uso terapéutico , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/uso terapéutico , Canales de Sodio/metabolismo , Animales , Línea Celular , Enfermedad Crónica , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Dolor/inmunología , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Nervios Espinales/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A new series of DPP-4 inhibitors derived from piperidine-fused benzimidazoles and imidazopyridines is described. Optimization of this class of DPP-4 inhibitors led to the discovery of imidazopyridine 34. The potency, selectivity, cross-species DMPK profiles, and in vivo efficacy of 34 is reported.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Imidazoles/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Cristalografía por Rayos X/métodos , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Diseño de Fármacos , Péptido 1 Similar al Glucagón/química , Humanos , Hidrólisis , Imidazoles/farmacología , Concentración 50 Inhibidora , Macaca mulatta , Ratones , Piperidinas/farmacología , Pirazinas/síntesis química , Pirazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Fosfato de Sitagliptina , Triazoles/síntesis química , Triazoles/farmacologíaRESUMEN
The synthesis, selectivity, rat pharmacokinetic profile, and drug metabolism profiles of a series of potent fluoroolefin-derived DPP-4 inhibitors (4) are reported. A radiolabeled fluoroolefin 33 was shown to possess a high propensity to form reactive metabolites, thus revealing a potential liability for this class of DPP-4 inhibitors.
Asunto(s)
Alquenos/farmacocinética , Amidas/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Hidrocarburos Fluorados/farmacocinética , Hipoglucemiantes/farmacocinética , Microsomas Hepáticos/efectos de los fármacos , Alquenos/síntesis química , Animales , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Hidrocarburos Fluorados/síntesis química , Hipoglucemiantes/síntesis química , Microsomas Hepáticos/patología , Modelos Químicos , Imitación Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
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.
Asunto(s)
Anticonvulsivantes/farmacología , Benzodiazepinonas/farmacología , Epilepsia/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Electrofisiología , Electrochoque , Epilepsia/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
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.
Asunto(s)
Piridinas/química , Piridinas/farmacología , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Analgésicos/química , Analgésicos/farmacología , Animales , Inflamación/tratamiento farmacológico , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7 , Dolor/tratamiento farmacológico , Ratas , Bloqueadores de los Canales de Sodio/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of substituted imidazopiperidine amides has been prepared and evaluated for inhibition of dipeptidyl peptidase IV (DPP-4). Substitution at the 1- and 3-positions produced increased selectivity for DPP-4 relative to DPP-8 and DPP-9. Compounds in this series had IC(50) values as low as 5.8 nM for inhibition of DPP-4.
Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV , Hipoglucemiantes/farmacología , Piperidinas/farmacología , Inhibidores de Proteasas/farmacología , Amidas/química , Humanos , Hipoglucemiantes/uso terapéutico , Piperidinas/química , Piperidinas/uso terapéutico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/uso terapéuticoRESUMEN
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.