RESUMO
The discovery of a novel peripherally acting and selective Cav3.2 T-type calcium channel blocker, ABT-639, is described. HTS hits 1 and 2, which have poor metabolic stability, were optimized to obtain 4, which has improved stability and oral bioavailability. Modification of 4 to further improve ADME properties led to the discovery of ABT-639. Following oral administration, ABT-639 produces robust antinociceptive activity in experimental pain models at doses that do not significantly alter psychomotor or hemodynamic function in the rat.
RESUMO
Activation of T-type Ca²âº channels contributes to nociceptive signaling by facilitating action potential bursting and modulation of membrane potentials during periods of neuronal hyperexcitability. The role of T-type Ca²âº channels in chronic pain is supported by gene knockdown studies showing that decreased Ca(v)3.2 channel expression results in the loss of low voltage-activated (LVA) currents in dorsal root ganglion (DRG) neurons and attenuation of neuropathic pain in the chronic constriction injury (CCI) model. ABT-639 is a novel, peripherally acting, selective T-type Ca²âº channel blocker. ABT-639 blocks recombinant human T-type (Ca(v)3.2) Ca²âº channels in a voltage-dependent fashion (IC50 = 2 µM) and attenuates LVA currents in rat DRG neurons (IC50 = 8 µM). ABT-639 was significantly less active at other Ca²âº channels (e.g. Ca(v)1.2 and Ca(v)2.2) (IC50 > 30 µM). ABT-639 has high oral bioavailability (%F = 73), low protein binding (88.9%) and a low brain:plasma ratio (0.05:1) in rodents. Following oral administration ABT-639 produced dose-dependent antinociception in a rat model of knee joint pain (ED50 = 2 mg/kg, p.o.). ABT-639 (10-100 mg/kg, p.o.) also increased tactile allodynia thresholds in multiple models of neuropathic pain (e.g. spinal nerve ligation, CCI, and vincristine-induced). [corrected]. ABT-639 did not attenuate hyperalgesia in inflammatory pain models induced by complete Freund's adjuvant or carrageenan. At higher doses (e.g. 100-300 mg/kg) ABT-639 did not significantly alter hemodynamic or psychomotor function. The antinociceptive profile of ABT-639 provides novel insights into the role of peripheral T-type (Ca(v)3.2) channels in chronic pain states.
Assuntos
Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Tipo T/metabolismo , Modelos Animais de Doenças , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuralgia/tratamento farmacológico , Dor Nociceptiva/tratamento farmacológico , Nervos Periféricos/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Disponibilidade Biológica , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/química , Canais de Cálcio Tipo T/genética , Células Cultivadas , Dor Crônica/tratamento farmacológico , Dor Crônica/metabolismo , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/efeitos adversos , Compostos Heterocíclicos com 2 Anéis/farmacocinética , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuralgia/metabolismo , Dor Nociceptiva/metabolismo , Nervos Periféricos/citologia , Nervos Periféricos/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 µM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 µM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Ensaios de Triagem em Larga Escala , Neoplasias Experimentais/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Quinase 1 Polo-LikeRESUMO
The synthesis of a novel series of 1,4-dihydroindeno[1,2-c]pyrazoles with acetylene-type side chains is described. Optimization of those compounds as KDR kinase inhibitors identified 8, which displayed an oral activity in an estradiol-induced murine uterine edema model (ED50 = 3 mg/kg) superior to Sutent (ED50 = 9 mg/kg) and showed potent antitumor efficacy in an MX-1 human breast carcinoma xenograft tumor growth model (tumor growth inhibition = 90% at 25 mg/kg.day po). The compound was docked into a homology model of the homo-tetrameric pore domain of the hERG potassium channel to identify strategies to improve its cardiac safety profile. Systematic interruption of key binding interactions between 8 and Phe656, Tyr652, and Ser624 yielded 90, which only showed an IC50 of 11.6 microM in the hERG patch clamp assay. The selectivity profile for 8 and 90 revealed that both compounds are multitargeted receptor tyrosine kinase inhibitors with low nanomolar potencies against the members of the VEGFR and PDGFR kinase subfamilies.
Assuntos
Alcinos/síntese química , Antineoplásicos/síntese química , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Indenos/síntese química , Pirazóis/síntese química , Receptores do Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Tiofenos/síntese química , Alcinos/efeitos adversos , Alcinos/farmacologia , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Ligação Competitiva , Linhagem Celular , Canal de Potássio ERG1 , Edema/induzido quimicamente , Edema/tratamento farmacológico , Estradiol , Canais de Potássio Éter-A-Go-Go/fisiologia , Feminino , Humanos , Indenos/efeitos adversos , Indenos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Técnicas de Patch-Clamp , Ligação Proteica , Pirazóis/efeitos adversos , Pirazóis/metabolismo , Pirazóis/farmacologia , Ensaio Radioligante , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacologia , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/tratamento farmacológico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Assuntos
Indenos/farmacologia , Pirazóis/farmacologia , Administração Oral , Animais , Química Farmacêutica , Desenho de Fármacos , Edema/patologia , Estradiol/farmacologia , Feminino , Indenos/química , Concentração Inibidora 50 , Camundongos , Modelos Químicos , Modelos Moleculares , Pirazóis/química , Relação Estrutura-Atividade , Útero/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/químicaRESUMO
A series of 1,4-dihydroindeno[1,2-c]pyrazoles with a 3-thiophene substituent carrying a urea-type side chain were identified as potent multitargeted (VEGFR and PDGFR families) receptor tyrosine kinase inhibitors. A KDR homology model suggested that the urea moiety is able to interact with a recognition motif in the hydrophobic specificity pocket of the enzyme.