RESUMEN
The orexin system consists of two neuropeptides (orexins A and B) and two receptors (OX1 and OX2). Selective OX1 receptor antagonists (SO1RA) are gaining interest for their potential use in the treatment of CNS disorders, including substance abuse, eating, obsessive compulsive, or anxiety disorders. While blocking OX2 reduces wakefulness, the expected advantage of selectively antagonizing OX1 is the ability to achieve clinical efficacy without the promotion of sleep. Herein we report our discovery efforts starting from a dual orexin receptor antagonist and describe a serendipitous finding that triggered a medicinal chemistry program that culminated in the identification of the potent SO1RA ACT-539313. Efficacy in a rat model of schedule-induced polydipsia supported the decision to select the compound as a preclinical candidate. Nivasorexant (20) represents the first SO1RA to enter clinical development and completed a first proof of concept phase II clinical trial in binge eating disorder in 2022.
Asunto(s)
Neuropéptidos , Ratas , Animales , Orexinas , Neuropéptidos/farmacología , Receptores de Orexina , Morfolinas , Antagonistas de los Receptores de Orexina/farmacología , Antagonistas de los Receptores de Orexina/uso terapéuticoRESUMEN
Selective orexin 2 receptor antagonists (2-SORA) such as seltorexant (15) are in clinical development for the treatment of insomnia and other conditions such as depression. Herein, we report our structure-activity-relationship (SAR) optimization efforts starting from an HTS hit (1) (N-(1-((5-acetylfuran-2-yl)methyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) that was derived from an unrelated in-house GPCR-agonist program. Medicinal chemistry efforts focused on the optimization of orexin 2 receptor (OX2R) antagonistic activity, stability in liver microsomes, time dependent CYP3A4 inhibition, and aqueous solubility. Compounds were assessed for their brain-penetrating potential in in vivo experiments to select the most promising compounds for our in vivo sleep model. Our lead optimization efforts led to the discovery of the potent, brain penetrating and orally active, 2-SORA (N-(1-(2-(5-methoxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide) 43 with efficacy in a sleep model in rats comparable to 15.
RESUMEN
Since its discovery in 1998, the orexin system has been of interest to the research community as a potential therapeutic target for the treatment of sleep/wake disorders, stress and anxiety disorders, addiction or eating disorders. It consists of two G protein-coupled receptors, the orexin 1 and orexin 2 receptors, and two neuropeptides with agonistic effects, the orexin A and orexin B peptides. Herein we describe our efforts leading to the identification of a promising set of dual orexin receptor antagonists (DORAs) which subsequently went through physiology-based pharmacokinetic and pharmacodynamic modelling>[1] and finally led to the selection of daridorexant, currently in phase 3 clinical trials for the treatment of insomnia disorders.
Asunto(s)
Imidazoles/farmacología , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Pirrolidinas/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/química , Estructura Molecular , Antagonistas de los Receptores de Orexina/química , Pirrolidinas/química , Trastornos del Inicio y del Mantenimiento del Sueño/metabolismoRESUMEN
The orexin system is responsible for regulating the sleep-wake cycle. Suvorexant, a dual orexin receptor antagonist (DORA) is approved by the FDA for the treatment of insomnia disorders. Herein, we report the optimization efforts toward a DORA, where our starting point was (5-methoxy-4-methyl-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-[5-(2-trifluoromethoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrrolidin-1-yl}methanone (6), a compound which emerged from our in-house research program. Compound 6 was shown to be a potent, brain-penetrating DORA with inâ vivo efficacy similar to suvorexant in rats. However, shortcomings from low metabolic stability, high plasma protein binding (PPB), low brain free fraction (fu brain), and low aqueous solubility, were identified and hence, compound 6 was not an ideal candidate for further development. Our optimization efforts addressing the above-mentioned shortcomings resulted in the identification of (4-chloro-2-[1,2,3]triazol-2-yl-phenyl)-{(S)-2-methyl-2-[5-(2-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-pyrrolidin-1-yl}l-methanone (42), a DORA with improved inâ vivo efficacy compared to 6.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Oxadiazoles/farmacología , Triazoles/farmacología , Animales , Perros , Masculino , Conformación Molecular , Antagonistas de los Receptores de Orexina/química , Oxadiazoles/química , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Estereoisomerismo , Triazoles/químicaRESUMEN
The orexin system plays an important role in the regulation of wakefulness. Suvorexant, a dual orexin receptor antagonist (DORA) is approved for the treatment of primary insomnia. Herein, we outline our optimization efforts toward a novel DORA. We started our investigation with rac-[3-(5-chloro-benzooxazol-2-ylamino)piperidin-1-yl]-(5-methyl-2-[1,2,3]triazol-2-ylphenyl)methanone (3), a structural hybrid of suvorexant and a piperidine-containing DORA. During the optimization, we resolved liabilities such as chemical instability, CYP3A4 inhibition, and low brain penetration potential. Furthermore, structural modification of the piperidine scaffold was essential to improve potency at the orexinâ 2 receptor. This work led to the identification of (5-methoxy-4-methyl-2-[1,2,3]triazol-2-ylphenyl)-{(S)-2-[5-(2-trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]pyrrolidin-1-yl}methanone (51), a potent, brain-penetrating DORA with inâ vivo efficacy similar to that of suvorexant in rats.
Asunto(s)
Antagonistas de los Receptores de Orexina/síntesis química , Receptores de Orexina/metabolismo , Oxadiazoles/química , Animales , Azepinas/farmacología , Citocromo P-450 CYP3A/química , Citocromo P-450 CYP3A/metabolismo , Perros , Semivida , Humanos , Concentración 50 Inhibidora , Antagonistas de los Receptores de Orexina/metabolismo , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/química , Oxadiazoles/metabolismo , Oxadiazoles/farmacología , Ratas , Sueño/efectos de los fármacos , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexinâ 1 and orexinâ 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacología , Descubrimiento de Drogas , Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Animales , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/síntesis química , Inhibidores del Citocromo P-450 CYP3A/química , Perros , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Ratas , Ratas Wistar , Sueño/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Starting from advanced pyrrolidin-2-one lead compounds, this novel series of small-molecule orexin receptor antagonists was further optimized by fine-tuning of the C-3 substitution at the γ-lactam ring. We discuss our design to align in vitro potency with metabolic stability and improved physicochemical/pharmacokinetic properties while avoiding P-glycoprotein-mediated efflux. These investigations led to the identification of the orally active 3-hydroxypyrrolidin-2-one 46, a potent and selective orexin-2 receptor antagonist, that achieved good brain exposure and promoted physiological sleep in rats.
Asunto(s)
Antagonistas de los Receptores de Orexina/farmacología , Receptores de Orexina/metabolismo , Pirrolidinonas/farmacología , Sueño/efectos de los fármacos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/administración & dosificación , Lactamas/farmacología , Estructura Molecular , Antagonistas de los Receptores de Orexina/síntesis química , Antagonistas de los Receptores de Orexina/química , Pirrolidinonas/síntesis química , Pirrolidinonas/química , Ratas , Relación Estructura-ActividadRESUMEN
The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.
Asunto(s)
Encéfalo/metabolismo , Neurotransmisores/química , Antagonistas de los Receptores de Orexina , Pirrolidinas/química , Sulfonamidas/química , Animales , Barrera Hematoencefálica/metabolismo , Perros , Semivida , Humanos , Células de Riñón Canino Madin Darby , Masculino , Neurotransmisores/farmacocinética , Receptores de Orexina/metabolismo , Prolina/química , Pirrolidinas/farmacocinética , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
Starting from a thiazolidin-4-one HTS hit, a novel series of substituted lactams was identified and developed as dual orexin receptor antagonists. In this Letter, we describe our initial efforts towards the improvement of potency and metabolic stability. These investigations delivered optimized lead compounds with CNS drug-like properties suitable for further optimization.
Asunto(s)
Descubrimiento de Drogas , Lactamas/farmacología , Antagonistas de los Receptores de Orexina , Animales , Relación Dosis-Respuesta a Droga , Humanos , Lactamas/química , Lactamas/metabolismo , Estructura Molecular , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Replacement of the dimethoxyphenyl moiety in the core skeleton of almorexant by appropriately substituted imidazoles afforded novel 1-chloro-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine derivatives as potent dual orexin receptor antagonists. We describe in this Letter our efforts to further optimize the potency and brain penetration of these derivatives by fine-tuning of the pivotal phenethyl motif, and we comment on the sleep-promoting activity of selected compounds in a rat electroencephalographic (EEG) model.
Asunto(s)
Imidazoles/farmacología , Antagonistas de los Receptores de Orexina , Pirazinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
A novel series of non-peptidic OX1R/OX2R orexin receptor antagonists was prepared by heterocyclic replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Introduction of substituted imidazole moieties delivered potent dual orexin receptor antagonists with nanomolar potency for hOX1R and hOX2R suitable for further fine-tuning. The preparation of these novel orexin receptor antagonists and the outcome of preliminary structure-activity relationship studies are described in this communication.
Asunto(s)
Pirazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Receptores de Orexina , Pirazinas/síntesis química , Pirazinas/química , Relación Estructura-ActividadRESUMEN
A novel series of dual orexin receptor antagonists was prepared by heteroaromatic five-membered ring system replacement of the dimethoxyphenyl moiety contained in the tetrahydroisoquinoline core skeleton of almorexant. Thus, replacement of the dimethoxyphenyl by a substituted pyrazole and additional optimization of the substitution pattern of the phenethyl motif allowed the identification of potent antagonists with low nanomolar affinity for hOX(1)R and hOX(2)R. The synthesis and structure-activity relationship of these novel antagonists will be discussed in this communication. These investigations furnished several suitable candidates for further evaluation in in vivo studies in rats.
Asunto(s)
Pirazoles/química , Piridinas/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Acetamidas/química , Acetamidas/farmacología , Animales , Isoquinolinas/química , Isoquinolinas/farmacología , Receptores de Orexina , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
New classes of de novo designed renin inhibitors are reported. Some of these compounds display excellent in vitro and in vivo activities toward human renin in a TGR model. The synthesis of these new types of mono- and bicyclic scaffolds are reported, and properties of selected compounds discussed.
Asunto(s)
Compuestos Bicíclicos con Puentes/clasificación , Compuestos Bicíclicos con Puentes/farmacología , Inhibidores Enzimáticos/clasificación , Inhibidores Enzimáticos/farmacología , Renina/antagonistas & inhibidores , Compuestos Bicíclicos con Puentes/química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.