RESUMEN

A series of 9-substituted fluorenols and 9,9'-disubstituted-9,9'-bifluorenyls were irradiated to give products derived from fluorenyl radicals. Product distribution was solvent dependent. A TEMPO adduct was isolated from the photoexcitation of 9-fluorenol. An unusual unsymmetrical 3,9'-bifluorenyl was observed from the photolysis of 9-trifluoromethylfluorenol and 9,9'-di(trifluoromethyl)-9,9'-bifluorenyl in more polar or hydrogen-bonding solvents. The electronic nature of 9-substituted fluorenyl radicals was probed using theoretical calculations showing the dipolar character of species with electron-deficient groups. These constitute the first examples of "doubly destabilized" radicals.

RESUMEN

We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K(+) channel inhibition (IC(50) = 4.7 µM) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure-activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F(po) = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain.

Asunto(s)

Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Trastornos Migrañosos/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Tiofenos/farmacología , Tiofenos/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Canal de Potasio ERG1 , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Ligadura/efectos adversos , Masculino , Trastornos Migrañosos/etiología , Ratas , Ratas Sprague-Dawley , Nervios Espinales/cirugía , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/uso terapéutico

RESUMEN

A family of different 3,5-disubstituted indole derivatives having 6-membered rings were designed, synthesized, and demonstrated inhibition of human nitric oxide synthase (NOS) with norepinephrine reuptake inhibitory activity (NERI). The structure-activity relationship (SAR) within the cyclohexane ring showed the cis-isomers to be more potent for neuronal NOS and selective over endothelial NOS compared to their trans-counterparts. Compounds, such as cis-(+)-37, exhibited dual nNOS and NET inhibition (IC(50) of 0.56 and 1.0 µM, respectively) and excellent selectivity (88-fold and 12-fold) over eNOS and iNOS, respectively. The lead compound (cis-(+)-37) showed lack of any direct vasoconstriction or inhibition of ACh-mediated vasorelaxation in isolated human coronary arteries. Additionally, cis-(+)-37 was effective at reversing both allodynia and thermal hyperalgesia in a standard Chung (spinal nerve ligation) rat neuropathic pain model. Overall, the data suggest that cis-(+)-37 is a promising dual action development candidate having therapeutic potential for the treatment of neuropathic pain.

Asunto(s)

Inhibidores de Captación Adrenérgica/síntesis química , Analgésicos/síntesis química , Indoles/síntesis química , Neuralgia/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Tiofenos/síntesis química , Inhibidores de Captación Adrenérgica/química , Inhibidores de Captación Adrenérgica/farmacología , Analgésicos/química , Analgésicos/farmacología , Animales , Células CHO , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Cricetinae , Cricetulus , Ciclohexanos/síntesis química , Ciclohexanos/química , Ciclohexanos/farmacología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Técnicas In Vitro , Indoles/química , Indoles/farmacología , Contracción Muscular , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Resistencia Vascular

RESUMEN

Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors, highlighted by 1 ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). Despite showing activity in two rodent pain models, 1 suffered from low oral bioavailability (18%) and moderate hERG channel inhibition (IC(50) = 4.7 µM). To optimize the properties of 1, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters. From these studies, we identified 47 as a potent and selective nNOS inhibitor with improved oral bioavailability (60%) and no hERG channel inhibition (IC(50) > 30 µM). Furthermore, 47 was efficacious in the Chung model of neuropathic pain and has an excellent safety profile, making it a promising preclinical development candidate.

Asunto(s)

Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Quinolinas/síntesis química , Tiofenos/síntesis química , Administración Oral , Analgésicos/síntesis química , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/fisiología , Ensayos Analíticos de Alto Rendimiento , Humanos , Neuralgia/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo I/fisiología , Técnicas de Placa-Clamp , Quinolinas/farmacocinética , Quinolinas/farmacología , Ratas , Bibliotecas de Moléculas Pequeñas , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacología

RESUMEN

A series of 1,6-disubstituted indoline derivatives were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS) designed to mitigate the cardiovascular liabilities associated with previously reported tetrahydroquinoline-based selective neuronal NOS inhibitors due to higher lipophilicity ( J. Med. Chem. 2011 , 54 , 5562 - 5575 ). This new series produced similar potency and selectivity among the NOS isoforms and was devoid of any cardiovascular liabilities associated with QT prolongation due to hERG activity or endothelial NOS mediated vasoconstriction effect. The SAR studies led to the identification of cis-45, which was shown to reverse thermal hyperalgesia in vivo in the spinal nerve ligation model of neuropathic pain with excellent safety profile (off-target activities at 80 CNS related receptors/ion channels/transporters). The results presented in this report make cis-45 as an ideal tool for evaluating the potential role of selective nNOS inhibitors in CNS related disorders where excess NO produced by nNOS is thought to play a crucial role.

Asunto(s)

Analgésicos/síntesis química , Sistema Cardiovascular/efectos de los fármacos , Indoles/síntesis química , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Tiofenos/síntesis química , Analgésicos/efectos adversos , Analgésicos/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/fisiología , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Células HEK293 , Ensayos Analíticos de Alto Rendimiento , Humanos , Técnicas In Vitro , Indoles/efectos adversos , Indoles/farmacología , Neuralgia/tratamiento farmacológico , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Técnicas de Placa-Clamp , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/efectos adversos , Tiofenos/farmacología , Resistencia Vascular , Vasoconstricción/efectos de los fármacos

RESUMEN

3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug-drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.

Asunto(s)

Analgésicos/síntesis química , Indoles/síntesis química , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Dolor/tratamiento farmacológico , Piridinas/síntesis química , Tiofenos/síntesis química , Analgésicos/química , Analgésicos/farmacología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Inhibidores Enzimáticos del Citocromo P-450 , Calor , Humanos , Hiperalgesia/tratamiento farmacológico , Indoles/química , Indoles/farmacología , Ligadura , Neuralgia/tratamiento farmacológico , Neuralgia/etiología , Piridinas/química , Piridinas/farmacología , Nervios Espinales/lesiones , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/farmacología , Resistencia Vascular , Vasoconstricción/efectos de los fármacos

RESUMEN

A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain.

Asunto(s)

Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Óxido Nítrico Sintasa/metabolismo , Estereoisomerismo , Relación Estructura-Actividad

RESUMEN

Neuronal nitric oxide synthase (nNOS) inhibitors are effective in preclinical models of many neurological disorders. In this study, two related series of compounds, 3,4-dihydroquinolin-2(1H)-one and 1,2,3,4-tetrahydroquinoline, containing a 6-substituted thiophene amidine group were synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). A structure-activity relationship (SAR) study led to the identification of a number of potent and selective nNOS inhibitors. Furthermore, a few representative compounds were shown to possess druglike properties, features that are often difficult to achieve when designing nNOS inhibitors. Compound (S)-35, with excellent potency and selectivity for nNOS, was shown to fully reverse thermal hyperalgesia when given to rats at a dose of 30 mg/kg intraperitonieally (ip) in the L5/L6 spinal nerve ligation model of neuropathic pain (Chung model). In addition, this compound reduced tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in a rat model of dural inflammation relevant to migraine pain.

Asunto(s)

Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Quinolinas/uso terapéutico , Animales , Humanos , Hiperalgesia/tratamiento farmacológico , Masculino , Trastornos Migrañosos/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad

RESUMEN

The photochemical pinacol reaction of a series of nonsymmetrical 9-fluorenyl-substituted vic-diols was investigated and compared with their acid-catalyzed thermal reaction. Unlike the thermal reaction, the radiation-induced processes involve only fluorenyl cations, as is reflected in differences of product distribution between the two reactions. From the product studies, substituent migratory aptitudes are reversed in the photochemical process, suggesting that kinetic control takes place under neutral conditions unlike the acid-catalyzed thermal reactions. The presence of fluorenyl cation intermediates and their lifetimes were established by laser flash spectroscopy studies.