RESUMO
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.
Assuntos
Ácidos Nicotínicos/química , Ácidos Nicotínicos/farmacologia , Antagonistas dos Receptores de Orexina , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Ácidos Nicotínicos/síntese química , Ácidos Nicotínicos/farmacocinética , Receptores de Orexina/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Amidas/química , EstereoisomerismoRESUMO
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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , RatosRESUMO
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.
Assuntos
Benzocicloeptenos/síntese química , Neurotransmissores/síntese química , Piridinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Benzocicloeptenos/química , Benzocicloeptenos/farmacologia , Linhagem Celular , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmissores/química , Neurotransmissores/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Acetamidas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Espiro/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Humanos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indóis/síntese química , Compostos de Espiro/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Humanos , Indóis/farmacologia , Macaca mulatta , Oxindóis , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos de Espiro/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/administração & dosagemRESUMO
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.
Assuntos
Amidas/farmacologia , Prolina/análogos & derivados , Prolina/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Amidas/síntese química , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Cinética , Neuropeptídeos/química , Neuropeptídeos/farmacologia , Receptores de Orexina , Orexinas , Prolina/síntese química , RatosRESUMO
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.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indanos/química , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Benzimidazóis/sangue , Benzimidazóis/química , Técnicas de Química Combinatória , Humanos , Macaca mulatta , Estrutura Molecular , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Pirimidinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cães , Feminino , Lobo Frontal/metabolismo , Humanos , Masculino , Medição da Dor , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
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 ifenprodilAssuntos
Membrana Celular/efeitos dos fármacos
, Antagonistas de Aminoácidos Excitatórios/química
, Antagonistas de Aminoácidos Excitatórios/farmacologia
, Ácido Glutâmico/metabolismo
, Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
, Transmissão Sináptica/efeitos dos fármacos
, Animais
, Sítios de Ligação/efeitos dos fármacos
, Sítios de Ligação/fisiologia
, Ligação Competitiva/efeitos dos fármacos
, Ligação Competitiva/fisiologia
, Sinalização do Cálcio/efeitos dos fármacos
, Sinalização do Cálcio/fisiologia
, Proteínas de Transporte/antagonistas & inibidores
, Proteínas de Transporte/genética
, Proteínas de Transporte/metabolismo
, Linhagem Celular
, Membrana Celular/fisiologia
, Relação Dose-Resposta a Droga
, Humanos
, Cinética
, Potenciais da Membrana/efeitos dos fármacos
, Potenciais da Membrana/fisiologia
, Camundongos
, Estrutura Molecular
, Proteínas do Tecido Nervoso/antagonistas & inibidores
, Proteínas do Tecido Nervoso/genética
, Proteínas do Tecido Nervoso/metabolismo
, Técnicas de Patch-Clamp
, Piperidinas/farmacologia
, Ensaio Radioligante
, Receptores de N-Metil-D-Aspartato/genética
, Receptores de N-Metil-D-Aspartato/metabolismo
, Transmissão Sináptica/fisiologia
RESUMO
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.
RESUMO
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.
Assuntos
Analgésicos/síntese química , Benzimidazóis/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Encéfalo/metabolismo , Cálcio/metabolismo , Carragenina , Linhagem Celular , Cães , Feminino , Humanos , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Técnicas In Vitro , Masculino , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/fisiologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Hipnóticos e Sedativos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/síntese química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cães , Descoberta de Drogas , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Receptores de Orexina , Piperidinas/farmacocinética , Piperidinas/farmacologia , Ligação Proteica , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Sono , Distúrbios do Início e da Manutenção do Sono/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/farmacocinética , Triazóis/farmacologia , Vigília/efeitos dos fármacosRESUMO
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.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologiaRESUMO
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.
Assuntos
Azepinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Triazóis/farmacologia , Animais , Azepinas/síntese química , Azepinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Técnicas In Vitro , Masculino , Microssomos Hepáticos/metabolismo , Receptores de Orexina , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Receptores Acoplados a Proteínas G/genética , Receptores de Neuropeptídeos/genética , Sono/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Estereoisomerismo , Relação Estrutura-Atividade , Telemetria , Triazóis/síntese química , Triazóis/farmacocinética , Vigília/efeitos dos fármacosRESUMO
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.
Assuntos
Azepinas/química , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Azepinas/farmacocinética , Azepinas/uso terapêutico , Sistema Nervoso Central/efeitos dos fármacos , Receptores de Orexina , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo T/metabolismo , Regulação Alostérica/efeitos dos fármacos , Sítio Alostérico/efeitos dos fármacos , Animais , Bloqueadores dos Canais de Cálcio/química , Células Cultivadas , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.