RESUMO
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.
Assuntos
Coenzima A/metabolismo , Modelos Animais de Doenças , Neurodegeneração Associada a Pantotenato-Quinase/tratamento farmacológico , Ácido Pantotênico/análogos & derivados , Pró-Fármacos/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Linhagem Celular Tumoral , Humanos , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurodegeneração Associada a Pantotenato-Quinase/metabolismo , Ácido Pantotênico/farmacocinética , Ácido Pantotênico/farmacologia , Ácido Pantotênico/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Interferência de RNA , Ratos Sprague-Dawley , Especificidade da EspécieRESUMO
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.
Assuntos
Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Descoberta de Drogas , Pirrolidinas/farmacologia , Animais , Cristalografia por Raios X , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/química , Cães , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/química , Inibidores da Dipeptidil Peptidase IV/química , Compostos Heterocíclicos com 2 Anéis/química , Piranos/química , Sulfonamidas/química , Animais , Sítios de Ligação , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Cães , Meia-Vida , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piranos/síntese química , Piranos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
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
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.
RESUMO
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.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/química , Canais de Cálcio Tipo N/fisiologia , Dor Crônica/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Piperidinas/farmacologia , Sulfonamidas/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/síntese química , Bloqueadores dos Canais de Cálcio/farmacocinética , Canais de Cálcio Tipo N/metabolismo , Células Cultivadas , Cães , Humanos , Camundongos , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Técnicas de Patch-Clamp , Piperidinas/síntese química , Piperidinas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sulfonamidas/síntese química , Sulfonamidas/farmacocinética , Distribuição TecidualRESUMO
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.
Assuntos
Piridinas/química , Receptores da Bombesina/agonistas , Sulfonamidas/farmacologia , Compostos de Sulfonilureia/farmacologia , Animais , Disponibilidade Biológica , Ligação de Hidrogênio , Masculino , Ratos , Ratos Sprague-Dawley , Sulfonamidas/química , Sulfonamidas/farmacocinética , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinéticaRESUMO
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.
Assuntos
Cicloexanos/síntese química , Cicloexanos/farmacologia , Inibidores da Dipeptidil Peptidase IV/síntese química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Disponibilidade Biológica , Cicloexanos/farmacocinética , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Meia-Vida , Piperidinas/farmacocinética , RatosRESUMO
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.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo N/metabolismo , Indóis/uso terapêutico , Dor/tratamento farmacológico , Animais , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Cães , Haplorrinos , Humanos , Indóis/farmacocinética , Indóis/farmacologia , RatosRESUMO
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.
Assuntos
Compostos de Bifenilo/química , Neuralgia/tratamento farmacológico , Pirazóis/química , Bloqueadores dos Canais de Sódio/química , Canais de Sódio/química , Animais , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/uso terapêutico , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Atividade Motora/efeitos dos fármacos , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Bloqueadores dos Canais de Sódio/farmacocinética , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/metabolismoRESUMO
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
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.
Assuntos
Benzamidas/farmacologia , Inflamação , Canais de Sódio/metabolismo , Analgésicos/farmacologia , Animais , Linhagem Celular , Humanos , Hiperalgesia/patologia , Masculino , Canal de Sódio Disparado por Voltagem NAV1.7 , Degeneração Neural/patologia , Dor , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologiaRESUMO
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.
Assuntos
Isoxazóis/uso terapêutico , Dor/tratamento farmacológico , Bloqueadores dos Canais de Sódio/uso terapêutico , Canais de Sódio/metabolismo , Animais , Linhagem Celular , Doença Crônica , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Dor/imunologia , Ratos , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Nervos Espinhais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Isoxazóis/química , Isoxazóis/farmacologia , Bloqueadores dos Canais de Sódio/química , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Isoxazóis/uso terapêutico , Modelos Moleculares , Estrutura Molecular , Dor/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Bloqueadores dos Canais de Sódio/uso terapêutico , Nervos Espinhais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Química Farmacêutica/métodos , Inibidores da Dipeptidil Peptidase IV/síntese química , Imidazóis/síntese química , Piperidinas/química , Piperidinas/síntese química , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Cristalografia por Raios X/métodos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Cães , Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Hidrólise , Imidazóis/farmacologia , Concentração Inibidora 50 , Macaca mulatta , Camundongos , Piperidinas/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Fosfato de Sitagliptina , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
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.
Assuntos
Alcenos/farmacocinética , Amidas/química , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hidrocarbonetos Fluorados/farmacocinética , Hipoglicemiantes/farmacocinética , Microssomos Hepáticos/efeitos dos fármacos , Alcenos/síntese química , Animais , Inibidores da Dipeptidil Peptidase IV/síntese química , Hidrocarbonetos Fluorados/síntese química , Hipoglicemiantes/síntese química , Microssomos Hepáticos/patologia , Modelos Químicos , Mimetismo Molecular , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
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
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 novel series of 4-arylcyclohexylalanine DPP-4 inhibitors was synthesized and tested for inhibitory activity as well as selectivity over the related proline-specific enzymes DPP-8 and DPP-9. Optimization of this series led to 28 (DPP-4 IC(50)=4.8 nM), which showed an excellent pharmacokinetic profile across several preclinical species. Evaluation of 28 in an oral glucose tolerance test demonstrated that this compound effectively reduced glucose excursion in lean mice.
Assuntos
Alanina/análogos & derivados , Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/farmacologia , Administração Oral , Alanina/química , Alanina/farmacologia , Animais , Área Sob a Curva , Camundongos , Modelos Moleculares , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinéticaRESUMO
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.