RESUMEN
The orphan G-protein-coupled receptor GPR139 is highly expressed in the habenula, a small brain nucleus that has been linked to depression, schizophrenia (SCZ), and substance-use disorder. High-throughput screening and a medicinal chemistry structure-activity relationship strategy identified a novel series of potent and selective benzotriazinone-based GPR139 agonists. Herein, we describe the chemistry optimization that led to the discovery and validation of multiple potent and selective in vivo GPR139 agonist tool compounds, including our clinical candidate TAK-041, also known as NBI-1065846 (compound 56). The pharmacological characterization of these GPR139 agonists in vivo demonstrated GPR139-agonist-dependent modulation of habenula cell activity and revealed consistent in vivo efficacy to rescue social interaction deficits in the BALB/c mouse strain. The clinical GPR139 agonist TAK-041 is being explored as a novel drug to treat negative symptoms in SCZ.
Asunto(s)
Descubrimiento de Drogas , Proteínas del Tejido Nervioso/agonistas , Receptores Acoplados a Proteínas G/agonistas , Esquizofrenia/tratamiento farmacológico , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Estructura Molecular , Proteínas del Tejido Nervioso/deficiencia , Receptores Acoplados a Proteínas G/deficiencia , Relación Estructura-ActividadRESUMEN
Parkinson's disease (PD) is a chronic and progressive movement disorder with the urgent unmet need for efficient symptomatic therapies with fewer side effects. GPR6 is an orphan G-protein coupled receptor (GPCR) with highly restricted expression in dopamine receptor D2-type medium spiny neurons (MSNs) of the indirect pathway, a striatal brain circuit which shows aberrant hyperactivity in PD patients. Potent and selective GPR6 inverse agonists (IAG) were developed starting from a low-potency screening hit (EC50 = 43 µM). Herein, we describe the multiple parameter optimization that led to the discovery of multiple nanomolar potent and selective GPR6 IAG, including our clinical compound CVN424. GPR6 IAG reversed haloperidol-induced catalepsy in rats and restored mobility in the bilateral 6-OHDA-lesioned rat PD model demonstrating that inhibition of GPR6 activity in vivo normalizes activity in basal ganglia circuitry and motor behavior. CVN424 is currently in clinical development to treat motor symptoms in Parkinson's disease.
Asunto(s)
Descubrimiento de Drogas , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
GPR6 is an orphan G-protein-coupled receptor that has enriched expression in the striatopallidal, indirect pathway and medium spiny neurons of the striatum. This pathway is greatly impacted by the loss of the nigro-striatal dopaminergic neurons in Parkinson disease, and modulating this neurocircuitry can be therapeutically beneficial. In this study, we describe the in vitro and in vivo pharmacological characterization of (R)-1-(2-(4-(2,4-difluorophenoxy)piperidin-1-yl)-3-((tetrahydrofuran-3-yl)amino)-7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)ethan-1-one (CVN424), a highly potent and selective small-molecule inverse agonist for GPR6 that is currently undergoing clinical evaluation. CVN424 is brain-penetrant and shows dose-dependent receptor occupancy that attained brain 50% of receptor occupancy at plasma concentrations of 6.0 and 7.4 ng/ml in mice and rats, respectively. Oral administration of CVN424 dose-dependently increases locomotor activity and reverses haloperidol-induced catalepsy. Furthermore, CVN424 restored mobility in bilateral 6-hydroxydopamine lesion model of Parkinson disease. The presence and localization of GPR6 in medium spiny neurons of striatum postmortem samples from both nondemented control and patients with Parkinson disease were confirmed at the level of both RNA (using Nuclear Enriched Transcript Sort sequencing) and protein. This body of work demonstrates that CVN424 is a potent, orally active, and brain-penetrant GPR6 inverse agonist that is effective in preclinical models and is a potential therapeutic for improving motor function in patients with Parkinson disease. SIGNIFICANCE STATEMENT: CVN424 represents a nondopaminergic novel drug for potential use in patients with Parkinson disease.
Asunto(s)
Cuerpo Estriado , Animales , Hormonas Esteroides Gonadales , RatasRESUMEN
Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.
Asunto(s)
Anticonvulsivantes/farmacología , Descubrimiento de Drogas , Trastornos Migrañosos/prevención & control , Niacina/química , Convulsiones/tratamiento farmacológico , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Anticonvulsivantes/química , Agonistas de los Canales de Calcio/toxicidad , Humanos , Masculino , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Pirimidinonas/toxicidad , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamenteRESUMEN
We report the discovery of a novel series of 2-(3-alkoxy-1-azetidinyl) quinolines as potent and selective PDE10A inhibitors. Structure-activity studies improved the solubility (pH 7.4) and maintained high PDE10A activity compared to initial lead compound 3, with select compounds demonstrating good oral bioavailability. X-ray crystallographic studies revealed two distinct binding modes to the catalytic site of the PDE10A enzyme. An ex vivo receptor occupancy assay in rats demonstrated that this series of compounds covered the target within the striatum.
Asunto(s)
Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/metabolismo , Quinolinas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/química , Quinolinas/síntesis química , Quinolinas/química , Solubilidad , Relación Estructura-ActividadRESUMEN
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values <3 mg/kg.
Asunto(s)
Conducta Animal/efectos de los fármacos , Microsomas Hepáticos/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Canales Catiónicos TRPM/antagonistas & inhibidores , Tetrahidroisoquinolinas/farmacocinética , Animales , Dicroismo Circular , Frío , Perros , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Pirimidinonas/farmacología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Estereoisomerismo , Canales Catiónicos TRPM/metabolismo , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacología , Distribución TisularRESUMEN
We describe a systematic study of how macrocyclization in the P1-P3 region of hydroxyethylamine-based inhibitors of ß-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid ß-peptide (Aß)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Etilaminas/química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Catepsina D/metabolismo , Cristalografía por Rayos X , Células HEK293 , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/metabolismo , Unión Proteica , Estructura Terciaria de ProteínaRESUMEN
The synthesis and SAR of a series of BACE-1 hydroxyethyl amine inhibitors containing substitutions on a spirocyclobutyl moiety is described. Selectivity against cathepsin D, a related aspartyl protease with potential off target toxicity, and improved microsomal stability is exemplified.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Etilaminas/química , Inhibidores de Proteasas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Sitios de Unión , Dominio Catalítico , Catepsina D/antagonistas & inhibidores , Catepsina D/metabolismo , Simulación por Computador , Etilaminas/síntesis química , Etilaminas/uso terapéutico , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/uso terapéutico , Relación Estructura-ActividadRESUMEN
A series of potent hydroxyethyl amine (HEA) derived inhibitors of ß-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS ß-amyloid (Aß) in Sprague-Dawley rats following oral administration.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Encéfalo/efectos de los fármacos , Dioxolanos/síntesis química , Etilaminas/síntesis química , Fragmentos de Péptidos/metabolismo , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Cristalografía por Rayos X , Dioxolanos/farmacocinética , Dioxolanos/farmacología , Perros , Diseño de Fármacos , Etilaminas/farmacocinética , Etilaminas/farmacología , Humanos , Macaca mulatta , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Proteica , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-ß peptide (Aß) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aß levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Compuestos de Espiro/síntesis química , Tiazoles/síntesis química , Administración Oral , Péptidos beta-Amiloides/líquido cefalorraquídeo , Animales , Proteínas Sanguíneas/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Cristalografía por Rayos X , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Diseño de Fármacos , Humanos , Técnicas In Vitro , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Fragmentos de Péptidos/líquido cefalorraquídeo , Unión Proteica , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Porcinos , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
ß-Secretase inhibitors are potentially disease-modifying treatments for Alzheimer's disease. Previous efforts in our laboratory have resulted in hydroxyethylamine-derived inhibitors such as 1 with low nanomolar potency against ß-site amyloid precursor protein cleaving enzyme (BACE). When dosed intravenously, compound 1 was also shown to significantly reduce Aß40 levels in plasma, brain, and cerebral spinal fluid. Herein, we report further optimizations that led to the discovery of inhibitor 16 as a novel, potent, and orally efficacious BACE inhibitor.
RESUMEN
A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
Asunto(s)
Antineoplásicos/química , Isoquinolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Tiadiazoles/química , Tiazoles/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Dominio Catalítico , Cristalografía por Rayos X , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Isoquinolinas/síntesis química , Isoquinolinas/farmacocinética , Ratones , Neoplasias/tratamiento farmacológico , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacocinética , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
A general strategy for the total synthesis of the antitumor agent apoptolidin (1) is proposed, and the chemical synthesis of the defined key building blocks (4, 5, 6, 8, and 9) in their enantiomerically pure forms is described. The projected total synthesis calls for a dithiane coupling reaction to construct the C(20)-C(21) bond, a Stille coupling reaction to form the C(11)-C(12) bond, and a Yamaguchi macrolactonization to assemble the macrolide ring, as well as two glycosidation reactions to fuse the carbohydrate units onto the molecule. First and second generation syntheses to the required fragments for apoptolidin (1) are described.
Asunto(s)
Macrólidos/síntesis química , EstereoisomerismoRESUMEN
The total synthesis of apoptolidin (1) is reported together with the design, synthesis, and biological evaluation of a number of analogues. The assembly of key fragments 6 and 7 to vinyl iodide 3 via dithiane coupling technology was supplemented by a second generation route to this advanced intermediate involving a Horner-Wadsworth-Emmons coupling of fragments 22 and 25. The final stages of the synthesis featured a Stille coupling between vinyl iodide 3 and vinylstannane 2, a Yamaguchi lactonization, a number of glycosidations, and final deprotection. The developed synthetic technology was applied to the construction of several analogues including 74, 75, and 77 which exhibit significant bioactivity against tumor cells.
Asunto(s)
Macrólidos/síntesis química , Macrólidos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Glicósidos/síntesis química , Glicósidos/química , Humanos , Macrólidos/química , Modelos Moleculares , Neoplasias Ováricas/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
As part of the dramatic changes associated with the need for preparing compound libraries in pharmaceutical and agrochemical research laboratories, industry searches for new technologies that allow for the automation of synthetic processes. Since the pioneering work by Merrifield polymeric supports have been identified to play a key role in this field however, polymer-assisted solution-phase synthesis which utilizes immobilized reagents and catalysts has only recently begun to flourish. Polymer-assisted solution-phase synthesis has various advantages over conventional solution-phase chemistry, such as the ease of separation of the supported species from a reaction mixture by filtration and washing, the opportunity to use an excess of the reagent to force the reaction to completion without causing workup problems, and the adaptability to continuous-flow processes. Various strategies for employing functionalized polymers stoichiometrically have been developed. Apart from reagents that are covalently or ionically attached to the polymeric backbone and which are released into solution in the presence of a suitable substrate, scavenger reagents play an increasingly important role in purifying reaction mixtures. Employing functionalized polymers in solution-phase synthesis has been shown to be extremely useful in automated parallel synthesis and multistep sequences. So far, compound libraries containing as many as 88 members have been generated by using several polymer-bound reagents one after another. Furthermore, it has been demonstrated that complex natural products like the alkaloids (+/-)-oxomaritidine and (+/-)-epimaritidine can be prepared by a sequence of five and six consecutive polymer-assisted steps, respectively, and the potent analgesic compound (+/-)-epibatidine in twelve linear steps ten of which are based on functionalized polymers. These developments reveal the great future prospects of polymer-assisted solution-phase synthesis.