RESUMEN
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).
Asunto(s)
Antivirales , SARS-CoV-2 , Animales , Ratones , SARS-CoV-2/efectos de los fármacos , Humanos , Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Tratamiento Farmacológico de COVID-19 , Inhibidores de Proteasas/farmacología , COVID-19/virología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virologíaRESUMEN
Carbapenem-resistant Acinetobacter baumannii infections have limited treatment options. Synthesis, transport and placement of lipopolysaccharide or lipooligosaccharide (LOS) in the outer membrane of Gram-negative bacteria are important for bacterial virulence and survival. Here we describe the cerastecins, inhibitors of the A. baumannii transporter MsbA, an LOS flippase. These molecules are potent and bactericidal against A. baumannii, including clinical carbapenem-resistant Acinetobacter baumannii isolates. Using cryo-electron microscopy and biochemical analysis, we show that the cerastecins adopt a serpentine configuration in the central vault of the MsbA dimer, stalling the enzyme and uncoupling ATP hydrolysis from substrate flipping. A derivative with optimized potency and pharmacokinetic properties showed efficacy in murine models of bloodstream or pulmonary A. baumannii infection. While resistance development is inevitable, targeting a clinically unexploited mechanism avoids existing antibiotic resistance mechanisms. Although clinical validation of LOS transport remains undetermined, the cerastecins may open a path to narrow-spectrum treatment modalities for important nosocomial infections.
Asunto(s)
Infecciones por Acinetobacter , Acinetobacter baumannii , Antibacterianos , Proteínas Bacterianas , Lipopolisacáridos , Acinetobacter baumannii/efectos de los fármacos , Acinetobacter baumannii/metabolismo , Lipopolisacáridos/metabolismo , Animales , Infecciones por Acinetobacter/microbiología , Infecciones por Acinetobacter/tratamiento farmacológico , Ratones , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Transporte Biológico , Pruebas de Sensibilidad Microbiana , Humanos , Microscopía por Crioelectrón , Carbapenémicos/farmacología , Carbapenémicos/metabolismo , Modelos Animales de Enfermedad , Femenino , Transportadoras de Casetes de Unión a ATPRESUMEN
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.
Asunto(s)
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidasas/química , Invenciones , Inhibidores de Proteasas/farmacología , Amidas , Antivirales/farmacología , Antivirales/químicaRESUMEN
A focused SAR study was conducted on a series of N1-substituted pyrazolopyrimidinone PDE2 inhibitors to reveal compounds with excellent potency and selectivity. The series was derived from previously identified internal leads and designed to enhance steric interactions with key amino acids in the PDE2 binding pocket. Compound 26 was identified as a lead compound with excellent PDE2 selectivity and good physicochemical properties.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/farmacología , Pirimidinonas/farmacología , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinonas/síntesis química , Pirimidinonas/química , Relación Estructura-ActividadRESUMEN
Doravirine, a novel nonnucleoside reverse transcriptase inhibitor for the treatment of human immunodeficiency virus 1 (HIV-1), is predominantly cleared by cytochrome P450 (CYP) 3A4 and metabolized to an oxidative metabolite (M9). Coadministration with rifabutin, a moderate CYP3A4 inducer, decreased doravirine exposure. Based on nonparametric superposition modeling, a doravirine dose adjustment from 100 mg once daily to 100 mg twice daily during rifabutin coadministration was proposed. However, M9 exposure may also be impacted by induction, in addition to the dose adjustment. As M9 concentrations have not been quantified in previous clinical studies, a physiologically based pharmacokinetic model was developed to investigate the change in M9 exposure when doravirine is coadministered with CYP3A inducers. Simulations demonstrated that although CYP3A induction increases doravirine clearance by up to 4.4-fold, M9 exposure is increased by only 1.2-fold relative to exposures for doravirine 100 mg once daily in the absence of CYP3A induction. Thus, a 2.4-fold increase in M9 exposure relative to the clinical dose of doravirine is anticipated when doravirine 100 mg twice daily is coadministered with rifabutin. In a subsequent clinical trial, doravirine and M9 exposures, when doravirine 100 mg twice daily was coadministered with rifabutin, were found to be consistent with model predictions using rifampin and efavirenz as representative inducers. These findings support the dose adjustment to doravirine 100 mg twice daily when coadministered with rifabutin.
Asunto(s)
Modelos Biológicos , Piridonas/farmacocinética , Inhibidores de la Transcriptasa Inversa/farmacocinética , Rifabutina/farmacología , Triazoles/farmacocinética , Adulto , Alquinos/farmacología , Benzoxazinas/farmacología , Simulación por Computador , Ciclopropanos/farmacología , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Inductores del Citocromo P-450 CYP3A/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piridonas/administración & dosificación , Inhibidores de la Transcriptasa Inversa/administración & dosificación , Rifabutina/administración & dosificación , Rifampin/farmacología , Triazoles/administración & dosificación , Adulto JovenRESUMEN
Drug-induced liver injury is a major reason for drug candidate attrition from development, denied commercialization, market withdrawal, and restricted prescribing of pharmaceuticals. The metabolic bioactivation of drugs to chemically reactive metabolites (CRMs) contribute to liver-associated adverse drug reactions in humans that often goes undetected in conventional animal toxicology studies. A challenge for pharmaceutical drug discovery has been reliably selecting drug candidates with a low liability of forming CRM and reduced drug-induced liver injury potential, at projected therapeutic doses, without falsely restricting the development of safe drugs. We have developed an in vivo rat liver transcriptional signature biomarker reflecting the cellular response to drug bioactivation. Measurement of transcriptional activation of integrated nuclear factor erythroid 2-related factor 2 (NRF2)/Kelch-like ECH-associated protein 1 (KEAP1) electrophilic stress, and nuclear factor erythroid 2-related factor 1 (NRF1) proteasomal endoplasmic reticulum (ER) stress responses, is described for discerning estimated clinical doses of drugs with potential for bioactivation-mediated hepatotoxicity. The approach was established using well benchmarked CRM forming test agents from our company. This was subsequently tested using curated lists of commercial drugs and internal compounds, anchored in the clinical experience with human hepatotoxicity, while agnostic to mechanism. Based on results with 116 compounds in short-term rat studies, with consideration of the maximum recommended daily clinical dose, this CRM mechanism-based approach yielded 32% sensitivity and 92% specificity for discriminating safe from hepatotoxic drugs. The approach adds new information for guiding early candidate selection and informs structure activity relationships (SAR) thus enabling lead optimization and mechanistic problem solving. Additional refinement of the model is ongoing. Case examples are provided describing the strengths and limitations of the approach.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Preparaciones Farmacéuticas , Animales , Desarrollo de Medicamentos , Proteína 1 Asociada A ECH Tipo Kelch , Masculino , Factor 2 Relacionado con NF-E2/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Regulatory agencies currently recommend itraconazole (ITZ) as a strong cytochrome P450 3A (CYP3A) inhibitor for clinical drug-drug interaction (DDI) studies. This work by an International Consortium for Innovation and Quality in Pharmaceutical Development working group (WG) is to develop and verify a mechanistic ITZ physiologically-based pharmacokinetic model and provide recommendations for optimal DDI study design based on model simulations. To support model development and verification, in vitro and clinical PK data for ITZ and its metabolites were collected from WG member companies. The model predictions of ITZ DDIs with seven different CYP3A substrates were within the guest criteria for 92% of area under the concentration-time curve ratios and 95% of maximum plasma concentration ratios, thus verifying the model for DDI predictions. The verified model was used to simulate various clinical DDI study scenarios considering formulation, duration of dosing, dose regimen, and food status to recommend the optimal design for maximal inhibitory effect by ITZ.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Itraconazol/farmacocinética , Área Bajo la Curva , Cálculo de Dosificación de Drogas , Interacciones Farmacológicas , Interacciones Alimento-Droga , Humanos , Itraconazol/farmacología , Modelos EstadísticosRESUMEN
We have identified a novel PDE2 inhibitor series using fragment-based screening. Pyrazolopyrimidine fragment 1, while possessing weak potency (Kiâ¯=â¯22.4⯵M), exhibited good binding efficiencies (LBEâ¯=â¯0.49, LLEâ¯=â¯4.48) to serve as a start for structure-based drug design. With the assistance of molecular modeling and X-ray crystallography, this fragment was developed into a series of potent PDE2 inhibitors with good physicochemical properties. Compound 16, a PDE2 selective inhibitor, was identified that exhibited favorable rat pharmacokinetic properties.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores de Fosfodiesterasa/química , Animales , Sitios de Unión , Dominio Catalítico , Cristalografía por Rayos X , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 2/metabolismo , Semivida , Humanos , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Conformación Molecular , Simulación de Dinámica Molecular , Inhibidores de Fosfodiesterasa/metabolismo , Inhibidores de Fosfodiesterasa/farmacocinética , Pirazoles/química , Pirazoles/metabolismo , Pirazoles/farmacocinética , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
A series of substituted indoles were examined as selective inhibitors of tropomyosin-related kinase receptor A (TrkA), a therapeutic target for the treatment of pain. An SAR optimization campaign based on ALIS screening lead compound 1 is reported.
Asunto(s)
Diseño de Fármacos , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Receptor trkA/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Receptor trkA/metabolismo , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Orexinas/antagonistas & inhibidores , Animales , Electroencefalografía , Electromiografía , Estructura Molecular , Antagonistas de los Receptores de Orexina/química , RatasRESUMEN
While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.
Asunto(s)
Antagonistas de los Receptores de Orexina/química , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Piperidinas/química , Piperidinas/farmacología , Animales , Descubrimiento de Drogas , Humanos , Piperidinas/farmacocinética , Ratas , Ratas Transgénicas , Relación Estructura-ActividadRESUMEN
Antagonism of orexin receptors has shown clinical efficacy as a novel paradigm for the treatment of insomnia and related disorders. Herein, molecules related to the dual orexin receptor antagonist filorexant were transformed into compounds that were selective for the OX2R subtype. Judicious selection of the substituents on the pyridine ring and benzamide groups led to 6b; which was highly potent, OX2R selective, and exhibited excellent development properties.
Asunto(s)
Antagonistas de los Receptores de Orexina/química , Receptores de Orexina/química , Piperidinas/química , Triazoles/química , Animales , Perros , Semivida , Ratones , Antagonistas de los Receptores de Orexina/farmacocinética , Antagonistas de los Receptores de Orexina/uso terapéutico , Receptores de Orexina/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Unión Proteica , Pirimidinas/química , Ratas , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Trastornos del Inicio y del Mantenimiento del Sueño/veterinaria , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/uso terapéuticoRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Pirimidinas/farmacología , Quinazolinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Pirimidinas/síntesis química , Pirimidinas/química , Quinazolinas/síntesis química , Quinazolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
Asunto(s)
Éteres/química , Antagonistas de los Receptores de Orexina , Piperidinas/química , Pirimidinas/química , Animales , Perros , Evaluación Preclínica de Medicamentos , Éteres/síntesis química , Éteres/farmacocinética , Semivida , Humanos , Receptores de Orexina/metabolismo , Piperidinas/metabolismo , Unión Proteica , Pirimidinas/metabolismo , Ratas , Sueño/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
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/químicaRESUMEN
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.
Asunto(s)
Antagonistas de los Receptores de Orexina , Pirimidinas/química , Pirimidinas/farmacología , Sueño/efectos de los fármacos , Animales , Descubrimiento de Drogas , Humanos , Pirimidinas/síntesis química , Ratas , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológicoRESUMEN
Analogs of the dual orexin receptor antagonist filorexant were prepared. Replacement of the ether linkage proved highly sensitive toward modification with an acetylene linkage providing compounds with the best in vitro and in vivo potency profiles.
Asunto(s)
Acetileno/química , Antagonistas de los Receptores de Orexina , Piperidinas/farmacología , Pirimidinas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ratones , Ratones Noqueados , Estructura Molecular , Receptores de Orexina/deficiencia , Receptores de Orexina/metabolismo , Piperidinas/síntesis química , Piperidinas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The field of small-molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof-of-concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX1 R and OX2 R), termed dual orexin receptor antagonists (DORAs), affording late-stage development candidates including Merck's suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX1 R or OX2 R alone has been hampered by the dearth of suitable subtype-selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2-SORA) series to afford a potent, orally bioavailable 2-SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5-disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P-glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2-SORA clinical candidate, 5''-chloro-N-[(5,6-dimethoxypyridin-2-yl)methyl]-2,2':5',3''-terpyridine-3'-carboxamide (MK-1064), in mouse, rat, dog, and rhesus sleep models.
Asunto(s)
Diseño de Fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Neuropéptidos/antagonistas & inhibidores , Piridinas/química , Piridinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Perros , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptidos/metabolismo , Orexinas , Ratas , Ratas Sprague-Dawley , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismoRESUMEN
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
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.