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1.
Bioorg Med Chem Lett ; 24(20): 4884-90, 2014 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-25248679

RESUMEN

Orexin receptor antagonists have demonstrated clinical utility for the treatment of insomnia. The majority of clinical efforts to date have focused on the development of dual orexin receptor antagonists (DORAs), small molecules that antagonize both the orexin 1 and orexin 2 receptors. Our group has recently disclosed medicinal chemistry efforts to identify highly potent, orally bioavailable selective orexin 2 receptor antagonists (2-SORAs) that possess acceptable profiles for clinical development. Herein we report additional SAR studies within the 'triaryl' amide 2-SORA series focused on improvements in compound stability in acidic media and time-dependent inhibition of CYP3A4. These studies resulted in the discovery of 2,5-disubstituted isonicotinamide 2-SORAs such as compound 24 that demonstrated improved stability and TDI profiles as well as excellent sleep efficacy across species.


Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina , Piridinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Tiazoles/farmacología , Animales , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química
2.
Bioorg Med Chem Lett ; 21(6): 1692-6, 2011 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-21316226

RESUMEN

A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.


Asunto(s)
Amidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Animales , Ratones , Ratas , Ratas Wistar
3.
J Pharmacol Exp Ther ; 335(2): 409-17, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20682849

RESUMEN

T-type calcium channels have been implicated in many behaviorally important neurophysiological processes, and altered channel activity has been linked to the pathophysiology of neurological disorders such as insomnia, epilepsy, Parkinson's disease, depression, schizophrenia, and pain. We have previously identified a number of potent and selective T-type channel antagonists (Barrow et al., 2007; Shipe et al., 2008; Yang et al., 2008). Here we describe the properties of the antagonist TTA-A2 [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)oxo]-pyridin-2-yl}ethyl)acetamide], assessed in patch-clamp experiments. TTA-A2 blocks T-type channels (Ca(v)3.1, 3.2, 3.3) voltage dependently and with high potency (IC(50) ∼100 nM). Stimulation at 3 Hz revealed additional use dependence of inhibition. A hyperpolarized shift of the channel availability curve and delayed channel recovery from inactivation suggest that the compound preferentially interacts with and stabilizes inactivated channels. The compound showed a ∼300-fold selectivity for Ca(v)3 channels over high-voltage activated calcium channels. Inhibitory effects on native T-type currents were confirmed in brain slice recordings from the dorsal lateral geniculate nucleus and the subthalamic nucleus. Furthermore, we demonstrate that in vivo T-type channel inhibition by TTA-A2 suppresses active wake and promotes slow-wave sleep in wild-type mice but not in mice lacking both Ca(v)3.1 and Ca(v)3.3, suggesting the selective effect of TTA-A2 on recurrent thalamocortical network activity. The discovery of the potent and selective T-type channel antagonist TTA-A2 has enabled us to study the in vivo effects of pharmacological T-channel inhibition on arousal in mice, and it will help to explore the validity of these channels as potential drug targets for sleep-related and other neurological diseases.


Asunto(s)
Nivel de Alerta/efectos de los fármacos , Bencenoacetamidas/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Piridinas/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Bencenoacetamidas/química , Bencenoacetamidas/uso terapéutico , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/uso terapéutico , Canales de Calcio Tipo T/genética , Línea Celular , Clonación Molecular , Relación Dosis-Respuesta a Droga , Cuerpos Geniculados/efectos de los fármacos , Cuerpos Geniculados/metabolismo , Humanos , Activación del Canal Iónico/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Técnicas de Placa-Clamp , Piridinas/química , Piridinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Trastornos del Despertar del Sueño/tratamiento farmacológico , Trastornos del Despertar del Sueño/metabolismo
4.
Bioorg Med Chem Lett ; 20(3): 1173-6, 2010 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-20022493

RESUMEN

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.


Asunto(s)
Dipéptidos/química , Dipéptidos/metabolismo , Integrina alfa4beta1/antagonistas & inhibidores , Prolina/química , Prolina/metabolismo , Animales , Unión Competitiva/fisiología , Dipéptidos/farmacología , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/metabolismo , Compuestos Heterocíclicos/farmacología , Humanos , Integrina alfa4beta1/metabolismo , Prolina/farmacología , Unión Proteica/fisiología , Ratas
5.
Bioorg Med Chem Lett ; 20(17): 5147-52, 2010 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-20673719

RESUMEN

The discovery and synthesis of 4,4-disubstituted quinazolinones as T-type calcium channel antagonists is reported. Based on lead compounds 2 and 3, a focused SAR campaign driven by the optimization of potency, metabolic stability, and pharmacokinetic profile identified 45 as a potent T-type Ca(2+) channel antagonist with minimized PXR activation. In vivo, 45 suppressed seizure frequency in a rat model of absence epilepsy and showed significant alterations of sleep architecture after oral dosing to rats as measured by EEG.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Quinazolinonas/química , Quinazolinonas/farmacología , Animales , Disponibilidad Biológica , Bloqueadores de los Canales de Calcio/química , Bloqueadores de los Canales de Calcio/farmacocinética , Cromatografía Líquida de Alta Presión , Descubrimiento de Drogas , Haplorrinos , Humanos , Quinazolinonas/farmacocinética , Ratas , Relación Estructura-Actividad
6.
ACS Med Chem Lett ; 1(2): 75-9, 2010 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-24900180

RESUMEN

A novel series of quinazolinone T-type calcium channel antagonists have been prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 by modifications of the 3- and 4-positions of the quinazolinone ring afforded potent and selective antagonists that displayed in vivo central nervous system efficacy in epilepsy and tremor models, as well as significant effects on rat active wake as measured by electrocorticogram.

7.
ACS Med Chem Lett ; 1(9): 504-9, 2010 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-24900239

RESUMEN

A novel phenyl acetamide series of short-acting T-type calcium channel antagonists has been identified and evaluated using in vitro and in vivo assays. Heterocycle substitutions of the 4-position of the phenyl acetamides afforded potent and selective antagonists that exhibited desired short plasma half-lives across preclinical species. Lead compound TTA-A8 emerged as a compound with excellent in vivo efficacy as indicated by its significant modulation of rat sleep architecture in an EEG telemetry model, favorable pharmacokinetic properties, and excellent preclinical safety. TTA-A8 recently progressed into human clinical trials, and in line with our predictions, preliminary studies (n = 12) with a 20 mg oral dose afforded a high C max of 1.82 ± 0.274 µM with an apparent terminal half-life of 3.0 ± 1.1 h.

8.
Vet Immunol Immunopathol ; 130(1-2): 79-87, 2009 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-19250687

RESUMEN

The purpose of this study was to characterize the alpha(4)beta(1) receptor (CD49d/CD29, very late antigen-4, VLA-4) on circulating equine leukocytes and to evaluate the intrinsic potency of an alpha(4)beta(1) receptor antagonist (Compound B) in the horse. Ultimately, these studies would allow us to determine the suitability of treating recurrent airway obstruction (RAO; heaves) affected horses by blocking the cellular recruitment of lymphocytes and neutrophils into the lung. The data demonstrates the alpha(4)beta(1) integrin is present on horse lymphocytes and neutrophils (fluorescence-assisted cell sorter, FACS) and can bind low molecular weight alpha(4)beta(1) antagonists (Compounds A and B) with high affinity. K(D) values for the binding of Compound A to non-activated alpha(4)beta(1) on isolated horse PBMCs (peripheral blood mononuclear cells) and activated neutrophils were 17 pM and 27 pM, respectively. Compound B was identified as a suitable antagonist for performing a series of in vivo experiments. Compound B was found to possess excellent potency in horse whole blood, possessing IC(50) and IC(90) values of 39 pM and 172 pM, respectively. This represents a 3.9-fold molar excess of drug over the alpha(4)beta(1) concentration in blood. Following oral administration of Compound B (5 mg/kg) to beagle dogs and rhesus monkeys, rapid and sustained alpha(4)beta(1) receptor occupancy (>80%) was achieved and maintained for a period of 24 h. When Compound B was administered intravenously to the horse, by either a slow or rapid infusion at a dose of 0.3 mg/kg, receptor blockade of >80% was observed out to 24 h with a concomitant leukocytosis. We believe that Compound B possesses suitable intrinsic and pharmacological properties to be evaluated clinically in horses affected by RAO.


Asunto(s)
Obstrucción de las Vías Aéreas/veterinaria , Enfermedades de los Caballos/inmunología , Integrina alfa4beta1/inmunología , Leucocitos/inmunología , Obstrucción de las Vías Aéreas/sangre , Obstrucción de las Vías Aéreas/tratamiento farmacológico , Obstrucción de las Vías Aéreas/inmunología , Animales , Unión Competitiva , Perros , Femenino , Citometría de Flujo/veterinaria , Enfermedades de los Caballos/sangre , Enfermedades de los Caballos/tratamiento farmacológico , Caballos , Integrina alfa4beta1/antagonistas & inhibidores , Macaca mulatta , Masculino , Ratas , Ratas Sprague-Dawley
9.
J Clin Invest ; 119(6): 1659-67, 2009 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19451696

RESUMEN

The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking CaV3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet-induced weight gain, without changes in food intake or sensitivity to high-fat diet-induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet-induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Grasas de la Dieta/antagonistas & inhibidores , Aumento de Peso/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/química , Canales de Calcio Tipo T/deficiencia , Canales de Calcio Tipo T/genética , Grasas de la Dieta/farmacología , Masculino , Ratones , Ratones Noqueados , Estructura Molecular , Ratas
10.
Cell Biochem Biophys ; 55(2): 81-93, 2009.
Artículo en Inglés | MEDLINE | ID: mdl-19582593

RESUMEN

Low-voltage-activated (T-type) calcium channels play a role in diverse physiological responses including neuronal burst firing, hormone secretion, and cell growth. To better understand the biological role and therapeutic potential of the target, a number of structurally diverse antagonists have been identified. Multiple drug interaction sites have been identified for L-type calcium channels, suggesting a similar possibility exists for the structurally related T-type channels. Here, we radiolabel a novel amide T-type calcium channel antagonist (TTA-A1) and show that several known antagonists, including mibefradil, flunarizine, and pimozide, displace binding in a concentration-dependent manner. Further, we identify a novel quinazolinone T-type antagonist (TTA-Q4) that enhanced amide radioligand binding, increased affinity in a saturable manner and slowed dissociation. Functional evaluation showed these compounds to be state-dependent antagonists which show a positive allosteric interaction. Consistent with slowing dissociation, the duration of efficacy was prolonged when compounds were co-administered to WAG/Rij rats, a genetic model of absence epilepsy. The development of a T-type calcium channel radioligand has been used to demonstrate structurally distinct TTAs interact at allosteric sites and to confirm the potential for synergistic inhibition of T-type calcium channels with structurally diverse antagonists.


Asunto(s)
Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Regulación Alostérica/efectos de los fármacos , Sitio Alostérico/efectos de los fármacos , Animales , Bloqueadores de los Canales de Calcio/química , Células Cultivadas , Humanos , Masculino , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad
12.
Bioorg Med Chem Lett ; 12(6): 837-40, 2002 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-11958974

RESUMEN

A simple, straightforward approach for parallel suspension polymerization is described. This technique utilizes equipment common to most organic chemistry laboratories and should facilitate the custom synthesis of new polymers.


Asunto(s)
Polímeros/síntesis química , Resinas Sintéticas/síntesis química , Resinas Acrílicas/síntesis química , Técnicas Químicas Combinatorias , Reactivos de Enlaces Cruzados/química
13.
Arch Biochem Biophys ; 424(2): 219-25, 2004 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-15047194

RESUMEN

Glucuronide conjugation of xenobiotics containing a carboxylic acid moiety represents an important metabolic pathway for these compounds in humans. Several human UDP-glucuronosyltransferases (UGTs) have been shown to catalyze the formation of acyl-glucuronides, including UGT2B7, UGT1A3, and UGT1A9. In this study, recombinant expressed UGT isoforms were investigated with many structurally related carboxylic acid analogues, and the UGT rank order for catalyzing the glucuronidation of carboxylic acids was UGT2B7?UGT1A3 approximately UGT1A9. Despite being a poor substrate with UGT1A3, coumarin-3-carboxylic acid was not a substrate for any other UGT isoform tested in this study, suggesting that it could be a specific substrate for UGT1A3. Interestingly, UGT1A7 and UGT1A10 also react with several carboxylic acid aglycones. Kinetic analysis showed that UGT2B7 exhibits much higher glucuronidation efficiency (Vmax/Km) with ibuprofen, ketoprofen, and others, compared to UGT1A3. These data indicate that UGT2B7 could be the major isoform involved in the glucuronidation of carboxylic acid compounds in humans.


Asunto(s)
Glucurónidos/química , Glucuronosiltransferasa/química , Riñón/enzimología , Tetrazoles/química , Ácidos Carboxílicos , Línea Celular , Activación Enzimática , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Isoenzimas/química , Riñón/embriología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Relación Estructura-Actividad , UDP Glucuronosiltransferasa 1A9
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