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1.
J Neurochem ; 142(2): 204-214, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28444767

RESUMO

Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects. Given their distinct mechanism of action, the current work tested the hypothesis that DORAs and GABAA receptor modulators differentially regulate neurochemical pathways associated with differences in sleep architecture and cognitive performance induced by these pharmacological mechanisms. Our findings showed that DORA-22 suppresses the release of the wake neurotransmitter histamine in the lateral hypothalamus, prefrontal cortex, and hippocampus with no significant alterations in acetylcholine levels. In contrast, eszopiclone, commonly used as a GABAA modulator, inhibited acetylcholine secretion across brain regions with variable effects on histamine release depending on the extent of wakefulness induction. In normal waking rats, eszopiclone only transiently suppressed histamine secretion, whereas this suppression was more obvious under caffeine-induced wakefulness. Compared with the GABAA modulator eszopiclone, DORA-22 elicits a neurotransmitter profile consistent with wake reduction that does not impinge on neurotransmitter levels associated with cognition and rapid eye movement sleep.


Assuntos
Acetilcolina/metabolismo , Hipocampo/efeitos dos fármacos , Histamina/metabolismo , Região Hipotalâmica Lateral/efeitos dos fármacos , Antagonistas dos Receptores de Orexina/farmacologia , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Triazóis/farmacologia , Animais , Hipocampo/metabolismo , Masculino , Córtex Pré-Frontal/metabolismo , Ratos , Sono/efeitos dos fármacos , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/fisiopatologia , Vigília/efeitos dos fármacos , Ácido gama-Aminobutírico/farmacologia
2.
Bioorg Med Chem Lett ; 27(10): 2087-2093, 2017 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-28389149

RESUMO

The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.


Assuntos
Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Nitrogênio/química , Dor/tratamento farmacológico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêutico
3.
Bioorg Med Chem Lett ; 27(6): 1364-1370, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28216403

RESUMO

In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX2R subtype and culminating in the discovery of 23, a highly potent, OX2R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX1R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed.


Assuntos
Antagonistas dos Receptores de Orexina/farmacologia , Orexinas/antagonistas & inibidores , Animais , Eletroencefalografia , Eletromiografia , Estrutura Molecular , Antagonistas dos Receptores de Orexina/química , Ratos
4.
Bioorg Med Chem Lett ; 25(21): 4992-4999, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25613676

RESUMO

Dual orexin receptor antagonists (DORAs), or orexin 1 (OX1) and orexin 2 (OX2) receptor antagonists, have demonstrated clinical utility for the treatment of insomnia. Medicinal chemistry efforts focused on the reduction of bioactivation potential of diazepane amide 1 through the modification of the Western heterocycle resulted in the discovery of suvorexant, a DORA recently approved by the FDA for the treatment of insomnia. A second strategy towards reducing bioactivation risk is presented herein through the exploration of monocyclic quinazoline isosteres, namely substituted pyrimidines. These studies afforded potent DORAs with significantly reduced bioactivation risk and efficacy in rodent sleep models. Surprisingly, side products from the chemistry used to produce these DORAs yielded isomeric pyrimidine-containing diazepane amides possessing selective OX2R antagonist (2-SORA) profiles. Additional exploration of these isomeric pyrimidines uncovered potent 2-SORA diazepane amides with sleep efficacy in mouse EEG studies.


Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Antagonistas dos Receptores de Orexina/síntese química , Antagonistas dos Receptores de Orexina/química , Pirimidinas/síntese química , Pirimidinas/química , Quinazolinas/síntese química , Quinazolinas/química , Ratos , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 24(9): 2079-85, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24704030

RESUMO

Recent clinical studies have demonstrated that dual orexin receptor antagonists (OX1R and OX2R antagonists or DORAs) represent a novel treatment option for insomnia patients. Previously we have disclosed several compounds in the diazepane amide DORA series with excellent potency and both preclinical and clinical sleep efficacy. Additional SAR studies in this series were enabled by the expansion of the acetonitrile-assisted, diphosgene-mediated 2,4-dichloropyrimidine synthesis to novel substrates providing an array of Western heterocycles. These heterocycles were utilized to synthesize analogs in short order with high levels of potency on orexin 1 and orexin 2 receptors as well as in vivo sleep efficacy in the rat.


Assuntos
Antagonistas dos Receptores de Orexina , Pirimidinas/química , Pirimidinas/farmacologia , Sono/efeitos dos fármacos , Animais , Descoberta de Drogas , Humanos , Pirimidinas/síntese química , Ratos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico
6.
Bioorg Med Chem Lett ; 24(20): 4884-90, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25248679

RESUMO

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.


Assuntos
Descoberta de Drogas , Antagonistas dos Receptores de Orexina , Piridinas/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiazóis/farmacologia , Animais , Cães , Relação Dose-Resposta a Droga , Humanos , Camundongos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
7.
ACS Med Chem Lett ; 15(1): 123-131, 2024 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-38229758

RESUMO

Inhibition of glucosylceramide synthase (GCS) has been proposed as a therapeutic strategy for the treatment of Parkinson's Disease (PD), particularly in patients where glycosphingolipid accumulation and lysosomal impairment are thought to be contributing to disease progression. Herein, we report the late-stage optimization of an orally bioavailable and CNS penetrant isoindolinone class of GCS inhibitors. Starting from advanced lead 1, we describe efforts to identify an improved compound with a lower human dose projection, minimal P-glycoprotein (P-gp) efflux, and acceptable pregnane X receptor (PXR) profile through fluorine substitution. Our strategy involved the use of predicted volume ligand efficiency to advance compounds with greater potential for low human doses down our screening funnel. We also applied minimized electrostatic potentials (Vmin) calculations for hydrogen bond acceptor sites to rationalize P-gp SAR. Together, our strategies enabled the alignment of a lower human dose with reduced P-gp efflux, and favorable PXR selectivity for the discovery of compound 12.

8.
J Med Chem ; 67(5): 3935-3958, 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38365209

RESUMO

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.


Assuntos
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidases/química , Invenções , Inibidores de Proteases/farmacologia , Amidas , Antivirais/farmacologia , Antivirais/química
9.
Bioorg Med Chem Lett ; 23(24): 6620-4, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24215892

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-Atividade
10.
ACS Med Chem Lett ; 14(7): 986-992, 2023 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-37465306

RESUMO

Modification of potent, selective metabotropic glutamate receptor 2 negative allosteric modulator (mGluR2 NAM) led to a series of analogues with excellent binding affinity, lipophilicity, and suitable physicochemical properties for a PET tracer with convenient chemical handles for incorporation of a 11C or 18F radiolabel. [11C]MK-8056 was synthesized and evaluated in vivo and demonstrated appropriate affinity, selectivity, and physicochemical properties to be used as a positron emission tomography tracer for mGluR2.

11.
ACS Med Chem Lett ; 14(2): 146-155, 2023 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-36793422

RESUMO

Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.

12.
J Med Chem ; 65(5): 3776-3785, 2022 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-35192762

RESUMO

Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at Merck & Co. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.


Assuntos
Química Farmacêutica , Descoberta de Drogas
13.
Channels (Austin) ; 16(1): 230-243, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36239534

RESUMO

As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function.


Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Insuficiência Respiratória , Animais , Dor , Nervo Frênico , Ratos , Insuficiência Respiratória/tratamento farmacológico
14.
ACS Med Chem Lett ; 12(6): 1038-1049, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34141090

RESUMO

The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.

15.
Bioorg Med Chem Lett ; 20(14): 4201-5, 2010 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-20610153

RESUMO

Orexins are excitatory neuropeptides that regulate arousal and sleep. Orexin receptor antagonists promote sleep and offer potential as a new therapy for the treatment of insomnia. In this Letter, we describe the synthesis of constrained diazepanes having a 3,9 diazabicyclo[4.2.1]nonane bicyclic core with good oral bioavailability and sleep-promoting activity in a rat EEG model.


Assuntos
Alcanos/farmacologia , Descoberta de Drogas , Hipnóticos e Sedativos/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Alcanos/química , Alcanos/farmacocinética , Animais , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Disponibilidade Biológica , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Eletroencefalografia , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/farmacocinética , Receptores de Orexina , Ratos , Ratos Sprague-Dawley
16.
Org Lett ; 22(4): 1648-1654, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31990565

RESUMO

Bicyclo[1.1.1]pentane motifs have gained increasing popularity in medicinal chemistry as bioisosteres because of their ability to impact key physicochemical properties. However, reports of direct C(sp2)-C(sp3) cross-coupling of these fragments to afford biaryl isosteres have been scarce. Herein we describe the development of continuous flow-enabled synthesis of bench-stable bicyclo[1.1.1]pentane trifluoroborate salts. Furthermore, we demonstrate the use of metallaphotoredox conditions to enable cross-coupling of these building blocks with complex aryl halide substrates.

17.
Bioorg Med Chem Lett ; 18(4): 1425-30, 2008 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-18207395

RESUMO

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 , Ratos
18.
Cancer Res ; 65(2): 605-12, 2005 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-15695405

RESUMO

Hypoxia-inducible factor 1 (HIF-1) is the central mediator of cellular responses to low oxygen and has recently become an important therapeutic target for solid tumor therapy. Inhibition of HIF-1 is expected to result in the attenuation of hypoxia-inducible genes, which are vital to many aspects of tumor biology, including adaptative responses for survival under anaerobic conditions. To identify small molecules inhibiting the HIF-1 pathway, we did a biological screen on a 10,000-membered natural product-like combinatorial library. The compounds of the library, which share a 2,2-dimethylbenzopyran structural motif, were tested for their ability to inhibit the hypoxic activation of an alkaline phosphatase reporter gene under the control of hypoxia-responsive elements in human glioma cells. This effort led to the discovery of 103D5R, a novel small-molecule inhibitor of HIF-1alpha. 103D5R markedly decreased HIF-1alpha protein levels induced by hypoxia or cobaltous ions in a dose- and time-dependent manner, whereas minimally affecting global cellular protein expression levels, including that of control proteins such as HIF-1beta, IkappaBalpha, and beta-actin. The inhibitory activity of 103D5R against HIF-1alpha was clearly shown under normoxia and hypoxia in cells derived from different cancer types, including glioma, prostate, and breast cancers. This inhibition prevented the activation of HIF-1 target genes under hypoxia such as vascular endothelial growth factor (VEGF) and glucose transporter-1 (Glut-1). Investigations into the molecular mechanism showed that 103D5R strongly reduced HIF-1alpha protein synthesis, whereas HIF-1alpha mRNA levels and HIF-1alpha degradation were not affected. 103D5R inhibited the phosphorylation of Akt, Erk1/2, and stress-activated protein kinase/c-jun-NH(2)-kinase, without changing the total levels of these proteins. Further studies on the mechanism of action of 103D5R will likely provide new insights into its validity/applicability for the pharmacologic targeting of HIF-1alpha for therapeutic purposes.


Assuntos
Benzopiranos/farmacologia , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Fatores Biológicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Técnicas de Química Combinatória , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Glioblastoma/tratamento farmacológico , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia , Masculino , Proteínas Nucleares/biossíntese , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/tratamento farmacológico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
19.
J Med Chem ; 59(2): 504-30, 2016 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-26317591

RESUMO

Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.


Assuntos
Hipnóticos e Sedativos/síntese química , Hipnóticos e Sedativos/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Antagonistas dos Receptores de Orexina/uso terapêutico , Receptores de Orexina/efeitos dos fármacos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Cães , Humanos , Camundongos , Modelos Moleculares , Narcolepsia/tratamento farmacológico , Ratos
20.
Nat Struct Mol Biol ; 23(4): 293-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26950369

RESUMO

The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R. The hOX1R structures also reveal a conserved amphipathic α-helix, in the extracellular N-terminal region, that interacts with orexin-A and is essential for high-potency neuropeptide activation at both receptors. The orexin-receptor crystal structures are valuable tools for the design and development of selective orexin-receptor antagonists and agonists.


Assuntos
Azepinas/farmacologia , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/química , Receptores de Orexina/metabolismo , Pirrolidinas/farmacologia , Tiazóis/farmacologia , Triazóis/farmacologia , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Conformação Proteica
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