RESUMEN
The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.
Asunto(s)
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacología , Antagonistas de los Receptores de Orexina , Animales , Perros , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Ácidos Nicotínicos/síntesis química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
Asunto(s)
Amidas/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Amidas/química , EstereoisomerismoRESUMEN
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Perros , Evaluación Preclínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , RatasRESUMEN
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Asunto(s)
Benzocicloheptenos/síntesis química , Neurotransmisores/síntesis química , Piridinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Benzocicloheptenos/química , Benzocicloheptenos/farmacología , Línea Celular , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmisores/química , Neurotransmisores/farmacología , Piridinas/química , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Relación Estructura-ActividadRESUMEN
A novel class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Asunto(s)
Acetamidas/química , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos de Espiro/química , Acetamidas/síntesis química , Acetamidas/farmacología , Animales , Línea Celular , Diseño de Fármacos , Humanos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indoles/síntesis química , Compuestos de Espiro/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Perros , Descubrimiento de Drogas , Humanos , Indoles/farmacología , Macaca mulatta , Oxindoles , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
Asunto(s)
Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos de Espiro/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Línea Celular , Perros , Haplorrinos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/química , Humanos , Ratas , Receptores de Péptido Relacionado con el Gen de Calcitonina/metabolismo , Compuestos de Espiro/administración & dosificaciónRESUMEN
A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole moiety within the lead structure significantly reduced P-gp susceptibility while increasing potency, giving rise to good brain penetration. A compound from this series has demonstrated in vivo central activity when dosed peripherally in a pharmacodynamic model of orexin activity.
Asunto(s)
Amidas/farmacología , Prolina/análogos & derivados , Prolina/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Amidas/síntesis química , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Péptidos y Proteínas de Señalización Intracelular/química , Péptidos y Proteínas de Señalización Intracelular/farmacología , Cinética , Neuropéptidos/química , Neuropéptidos/farmacología , Receptores de Orexina , Orexinas , Prolina/síntesis química , RatasRESUMEN
The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Indanos/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacología , Animales , Bencimidazoles/sangre , Bencimidazoles/química , Técnicas Químicas Combinatorias , Humanos , Macaca mulatta , Estructura Molecular , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Asunto(s)
Amidas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Amidas/química , Amidas/farmacocinética , Animales , Disponibilidad Biológica , Barrera Hematoencefálica , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Semivida , Humanos , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.
Asunto(s)
Analgésicos/síntesis química , Encéfalo/metabolismo , Pirimidinas/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Administración Oral , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Disponibilidad Biológica , Línea Celular , Perros , Femenino , Lóbulo Frontal/metabolismo , Humanos , Masculino , Dimensión del Dolor , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
N-Methyl-D-aspartate (NMDA) subunit specific receptor antagonism has potential therapeutic application for multiple CNS pathologies. MERCK 1, MERCK 2, and MERCK 3 are novel NR2B subtype selective NMDA receptor antagonists. The affinity and the kinetic mechanism of inhibition by these antagonists and ifenprodil were investigated using the whole-cell configuration of the patch clamp technique, calcium flux, and radioligand binding on a mouse cell line L(tk-) expressing recombinant human heteromeric NMDA receptors consisting of NR1a/NR2B subunit combinations. The rank order of potency, as determined by electrophysiology, was ifenprodilAsunto(s)
Membrana Celular/efectos de los fármacos
, Antagonistas de Aminoácidos Excitadores/química
, Antagonistas de Aminoácidos Excitadores/farmacología
, Ácido Glutámico/metabolismo
, Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores
, Transmisión Sináptica/efectos de los fármacos
, Animales
, Sitios de Unión/efectos de los fármacos
, Sitios de Unión/fisiología
, Unión Competitiva/efectos de los fármacos
, Unión Competitiva/fisiología
, Señalización del Calcio/efectos de los fármacos
, Señalización del Calcio/fisiología
, Proteínas Portadoras/antagonistas & inhibidores
, Proteínas Portadoras/genética
, Proteínas Portadoras/metabolismo
, Línea Celular
, Membrana Celular/fisiología
, Relación Dosis-Respuesta a Droga
, Humanos
, Cinética
, Potenciales de la Membrana/efectos de los fármacos
, Potenciales de la Membrana/fisiología
, Ratones
, Estructura Molecular
, Proteínas del Tejido Nervioso/antagonistas & inhibidores
, Proteínas del Tejido Nervioso/genética
, Proteínas del Tejido Nervioso/metabolismo
, Técnicas de Placa-Clamp
, Piperidinas/farmacología
, Ensayo de Unión Radioligante
, Receptores de N-Metil-D-Aspartato/genética
, Receptores de N-Metil-D-Aspartato/metabolismo
, Transmisión Sináptica/fisiología
RESUMEN
The preclinical pharmacodynamic and pharmacokinetic properties of 4-methylbenzyl (3S, 4R)-3-fluoro-4-[(Pyrimidin-2-ylamino) methyl] piperidine-1-carboxylate (CERC-301), an orally bioavailable selective N-methyl-D-aspartate (NMDA) receptor subunit 2B (GluN2B) antagonist, were characterized to develop a translational approach based on receptor occupancy (RO) to guide CERC-301 dose selection in clinical trials of major depressive disorder. CERC-301 demonstrated high-binding affinity (K i, 8.1 nmol L(-1)) specific to GluN2B with an IC 50 of 3.6 nmol L(-1) and no off-target activity. CERC-301 efficacy was demonstrated in the forced swim test with an efficacy dose (ED 50) of 0.3-0.7 mg kg(-1) (RO, 30-50%); increase in locomotor activity was observed at ED 50 of 2 mg kg(-1), corresponding to an RO of 75%. The predicted 50% RO concentration (Occ50) in humans was 400 nmol L(-1), similar to that predicted for rat, dog, and monkey (300, 200, and 400 nmol L(-1), respectively). Safety pharmacology and neurotoxicity studies raised no specific safety concerns. A first-in-human study in healthy males demonstrated a dose-proportional pharmacokinetic profile, with T max of ~1 h and t 1/2 of 12-17 h. Based on the preclinical and pharmacodynamic data, doses of ≥8 mg in humans are hypothesized to have an acceptable safety profile and result in clinically relevant peak plasma exposure.
RESUMEN
Two classes of 5-substituted benzimidazoles were identified as potent antagonists of the NR2B subtype of the N-methyl-d-aspartate (NMDA) receptor. Selected compounds show very good selectivity versus the NR2A, NR2C, and NR2D subtypes of the NMDA receptor as well as versus hERG-channel activity and alpha(1)-adrenergic binding. Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs.
Asunto(s)
Analgésicos/síntesis química , Bencimidazoles/síntesis química , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Encéfalo/metabolismo , Calcio/metabolismo , Carragenina , Línea Celular , Perros , Femenino , Humanos , Hiperalgesia/sangre , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Técnicas In Vitro , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiología , Relación Estructura-ActividadRESUMEN
Insomnia is a common disorder that can be comorbid with other physical and psychological illnesses. Traditional management of insomnia relies on general central nervous system (CNS) suppression using GABA modulators. Many of these agents fail to meet patient needs with respect to sleep onset, maintenance, and next-day residual effects and have issues related to tolerance, memory disturbances, and balance. Orexin neuropeptides are central regulators of wakefulness, and orexin antagonism has been identified as a novel mechanism for treating insomnia with clinical proof of concept. Herein we describe the discovery of a series of α-methylpiperidine carboxamide dual orexinâ 1 and orexinâ 2 receptor (OX(1) R/OX(2) R) antagonists (DORAs). The design of these molecules was inspired by earlier work from this laboratory in understanding preferred conformational properties for potent orexin receptor binding. Minimization of 1,3-allylic strain interactions was used as a design principle to synthesize 2,5-disubstituted piperidine carboxamides with axially oriented substituents including DORA 28. DORA 28 (MK-6096) has exceptional inâ vivo activity in preclinical sleep models, and has advanced into phaseâ II clinical trials for the treatment of insomnia.
Asunto(s)
Hipnóticos y Sedantes/síntesis química , Piperidinas/síntesis química , Piridinas/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Triazoles/síntesis química , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Perros , Descubrimiento de Drogas , Humanos , Hipnóticos y Sedantes/farmacocinética , Hipnóticos y Sedantes/farmacología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacología , Unión Proteica , Piridinas/farmacocinética , Piridinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Sueño , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacología , Vigilia/efectos de los fármacosRESUMEN
A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
Asunto(s)
Ciclopentanos/síntesis química , Ciclopentanos/farmacología , Descubrimiento de Drogas/métodos , Antagonistas de Aminoácidos Excitadores/síntesis química , Antagonistas de Aminoácidos Excitadores/farmacología , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Administración Oral , Animales , Benzopiranos/metabolismo , Disponibilidad Biológica , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Canales de Potasio Éter-A-Go-Go/metabolismo , Femenino , Semivida , Indicadores y Reactivos , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamiento farmacológico , Enfermedad de Parkinson/tratamiento farmacológico , Piperidinas/metabolismo , Ratas , Ratas Sprague-Dawley , Nervios Espinales/patologíaRESUMEN
Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquinazoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.
Asunto(s)
Azepinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Triazoles/farmacología , Animales , Azepinas/síntesis química , Azepinas/farmacocinética , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Perros , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Receptores de Orexina , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropéptido/genética , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Estereoisomerismo , Relación Estructura-Actividad , Telemetría , Triazoles/síntesis química , Triazoles/farmacocinética , Vigilia/efectos de los fármacosRESUMEN
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-ActividadRESUMEN
Silent Night: Antagonism of the orexin (or hypocretin) system has recently been identified as a novel mechanism for the treatment of insomnia. Herein, we describe discovery of a dual (OX(1)R/OX(2)R) orexin receptor antagonist featuring a 1,4-diazepane central constraint that blocks orexin signaling in vivo. In telemetry-implanted rats, oral administration of this antagonist produced a decrease in wakefulness, while increasing REM and non-REM sleep.
Asunto(s)
Azepinas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Azepinas/farmacocinética , Azepinas/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Receptores de Orexina , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.