RESUMEN
We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5â¯mg/kg/h.
Asunto(s)
Benzamidas/farmacología , Encéfalo/efectos de los fármacos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Piridazinas/farmacología , Benzamidas/síntesis química , Benzamidas/química , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Piridazinas/síntesis química , Piridazinas/química , Relación Estructura-ActividadRESUMEN
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100â¯mg/kg) and mice (45â¯mg/kg) following oral administration.
Asunto(s)
Descubrimiento de Drogas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Ratones , Estructura Molecular , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Pirimidinas/química , Ratas , Serina/antagonistas & inhibidores , Serina/metabolismo , Relación Estructura-ActividadRESUMEN
Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
Asunto(s)
Benzamidas/farmacología , Descubrimiento de Drogas , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Benzamidas/administración & dosificación , Benzamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
Starting from a orexin 1 receptor selective antagonist 4,4-disubstituted piperidine series a novel potent 5-azaspiro[2.4]heptane dual orexin 1 and orexin 2 receptor antagonist class has been discovered. SAR and Pharmacokinetic optimization of this series is herein disclosed. Lead compound 15 exhibits potent activity against orexin 1 and orexin 2 receptors along with low cytochrome P450 inhibition potential, good brain penetration and oral bioavailability in rats.
Asunto(s)
Compuestos Aza/química , Heptanos/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Compuestos de Espiro/química , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Heptanos/síntesis química , Heptanos/farmacocinética , Receptores de Orexina , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Relación Estructura-ActividadRESUMEN
Plasmepsin X (PMX) has been identified as a multistage antimalarial target. PMX is a malarial aspartyl protease essential for merozoite egress from infected red blood cells and invasion of the host erythrocytes. Previously, we reported the identification of PMX inhibitors by structure-based optimization of a cyclic guanidine core. Preclinical assessment of UCB7362, which displayed both in vitro and in vivo antimalarial activity, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime). We report here the efforts toward extending the half-life (t1/2) by reducing metabolic clearance and increasing volume of distribution (Vss). Our efforts culminated in the identification of a biaryl series, with an expected longer t1/2 in human than UCB7362 while maintaining a similar in vitro off-target hit rate.
RESUMEN
The construction of a EP(4) antagonists pharmacophore model and the discovery of a highly potent oxepinic series of EP(4) antagonists is discussed. Compound 1a exhibits an excellent selectivity profile toward EP(2) receptor subtype and low cytochrome P450 inhibition potential.
Asunto(s)
Benzoxepinas/síntesis química , Benzoxepinas/farmacología , Modelos Moleculares , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Benzoxepinas/química , Evaluación Preclínica de Medicamentos , Humanos , Técnicas In VitroRESUMEN
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Asunto(s)
Descubrimiento de Drogas , Piperidinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Receptores de Orexina , Piperidinas/síntesis química , Piperidinas/química , Ratas , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropéptido/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Asunto(s)
Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Antagonistas de la Serotonina/uso terapéutico , Trastornos del Sueño-Vigilia/tratamiento farmacológico , HumanosRESUMEN
Investigation of a series 6-[2-(4-aryl-1-piperazinyl)ethyl]-2H-1,4-benzoxazin-3(4H)-ones has led to the discovery of potent 5-HT(1A/1B/1D) receptor antagonists with and without additional SerT affinity. Modulation of the different target activities gave compounds with a range of profiles suitable for further in vivo characterization.
Asunto(s)
Benzoxazoles/síntesis química , Piperazinas/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/farmacología , Animales , Antidepresivos/síntesis química , Antidepresivos/farmacología , Benzoxazoles/farmacología , Diseño de Fármacos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Modelos Químicos , Piperazina , Piperazinas/química , Piperazinas/farmacología , Ratas , Antagonistas del Receptor de Serotonina 5-HT1RESUMEN
The involvement of Neuropeptide Y (NPY) in the pathophysiology of mood disorders has been suggested by clinical and preclinical evidence. NPY Y1 and Y2 receptors have been proposed to mediate the NPY modulation of stress responses and anxiety related behaviors. To further investigate the role of Y2 receptors in anxiety we studied the effect of BIIE0246, a selective Y2 receptor antagonist, in the elevated plus-maze test. Rats treated with 1.0 nmol BIIE0246 showed an increase in the time spent on the open arm of the maze. In addition, to study the effects of the Y2 antagonism on NPY protein level, NPY-like immunoreactivity was measured in different brain regions following treatment with BIIE0246, but no statistically significant effects were observed. These results suggest that BIIE0246 has an anxiolytic-like profile in the elevated plus-maze.
Asunto(s)
Ansiolíticos/farmacología , Arginina/análogos & derivados , Benzazepinas/farmacología , Actividad Motora/efectos de los fármacos , Receptores de Neuropéptido Y/antagonistas & inhibidores , Animales , Arginina/farmacología , Masculino , RatasRESUMEN
LRRK2 is a large multidomain protein containing two functional enzymatic domains: a GTPase domain and a protein kinase domain. Dominant coding mutations in the LRRK2 protein are associated with Parkinson's disease (PD). Among such pathogenic mutations, Gly2019Ser mutation in the LRRK2 kinase domain is the most frequent cause of familial PD in Caucasians and is also found in some apparently sporadic PD cases. This mutation results in 2- to 3-fold elevated LRRK2 kinase activity compared with wild type, providing a clear clinical hypothesis for the application of kinase inhibitors in the treatment of this disease. To date, reported screening assays for LRRK2 have been based on detection of labeled adenosine triphosphate and adenosine diphosphate or on antibody-based detection of phosphorylation events. While these assays do offer a high-throughput method of monitoring LRRK2 kinase activity, they are prone to interference from autofluorescent compounds and nonspecific events. Here we describe a label-free assay for LRRK2 kinase activity using the RapidFire mass spectrometry system. This assay format was found to be highly robust and enabled a screen of 100,000 lead-like small molecules. The assay successfully identified a number of known LRRK2 chemotypes that met stringent physicochemical criteria.
Asunto(s)
Enfermedad de Parkinson/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Línea Celular , ADN Complementario/genética , GTP Fosfohidrolasas/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Espectrometría de Masas/métodos , Mutación/genética , Fosforilación/genética , Estructura Terciaria de Proteína/genética , Células Sf9RESUMEN
Prostaglandin antagonists, with their pharmacological effects, are well-known drugs capable of treating widely diffused illnesses, including pain and inflammation disorders. In recent years, a major research focus has been devoted to the identification of agents able to selectively antagonize each receptor with which prostaglandins interact. This review attempts to give a broad overview of molecules capable of selectively blocking the prostaglandin PGE2 EP4 receptor. Further therapeutic applications and uses have also been disccussed, including the first drug candidate to have reached clinical trials within the last few years.
Asunto(s)
Antagonistas de Prostaglandina/farmacología , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Benzoatos/farmacología , Benzoatos/uso terapéutico , Humanos , Antagonistas de Prostaglandina/uso terapéutico , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Compuestos de Sulfonilurea/farmacología , Compuestos de Sulfonilurea/uso terapéuticoRESUMEN
As a further development of our large program focused on the medicinal chemistry of translocator protein [TSPO (18 kDa)] ligands, a new class of compounds related to alpidem has been designed using SSR180575, emapunil, and previously published pyrrolo[3,4-b]quinoline derivatives 9 as templates. The designed compounds were synthesized by alkylation of the easily accessible 4-methyl-2-phenyl-1H-pyrazolo[3,4-b]quinolin-3(2H)-one derivatives 13-15 with the required bromoacetamides. Along with the expected 2-(4-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazolo[3,4-b]quinolin-1-yl)acetamide derivatives 10, 2-(4-methyl-3-oxo-2-phenyl-2H-pyrazolo[3,4-b]quinolin-9(3H)-yl)acetamide isomers 11 were isolated and characterized. The high TSPO affinity shown by new pyrazolo[3,4-b]quinoline derivatives 10 and especially 11 leads the way to further expand the chemical diversity in TSPO ligands and provides new templates and structure-affinity relationship data potentially useful in the design of new anxiolytic and neuroprotective agents.
Asunto(s)
Ansiolíticos/síntesis química , Proteínas Portadoras/metabolismo , Modelos Moleculares , Pirazoles/síntesis química , Quinolinas/síntesis química , Receptores de GABA-A/metabolismo , Receptores de GABA/metabolismo , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Corteza Cerebral/metabolismo , Cristalografía por Rayos X , Humanos , Técnicas In Vitro , Ligandos , Masculino , Ratones , Mononeuropatías/tratamiento farmacológico , Pirazoles/química , Pirazoles/farmacología , Quinolinas/química , Quinolinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range.
Asunto(s)
Endopeptidasas/química , Indoles/química , Inhibidores de Proteasas/síntesis química , Quinolonas/química , Proteínas ADAM/química , Sitios de Unión , Dominio Catalítico , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Endopeptidasas/metabolismo , Indoles/síntesis química , Indoles/farmacología , Conformación Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Quinolonas/síntesis química , Quinolonas/farmacologíaRESUMEN
In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.
Asunto(s)
Imidazoles/farmacología , Quinolinas/farmacología , Antagonistas de la Serotonina/farmacología , Administración Oral , Animales , Células CHO , Cromatografía Liquida , Cricetulus , Descubrimiento de Drogas , Humanos , Imidazoles/administración & dosificación , Imidazoles/química , Espectroscopía de Resonancia Magnética , Masculino , Quinolinas/administración & dosificación , Quinolinas/química , Ratas Sprague-Dawley , Receptores de Serotonina/clasificación , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/química , Espectrometría de Masas en TándemRESUMEN
Histamine H(1) and serotonin 5-HT(2A) receptors mediate two different mechanisms involved in sleep regulation: H(1) antagonists are sleep inducers, while 5-HT(2A) antagonists are sleep maintainers. Starting from 9'a, a novel spirotetracyclic compound endowed with good H(1)/5-HT(2A) potency but poor selectivity, very high Cli, and a poor P450 profile, a specific optimization strategy was set up. In particular, we investigated the possibility of introducing appropriate amino acid moieties to optimize the developability profile of the series. Following this zwitterionic approach, we were able to identify several advanced leads (51, 65, and 73) with potent dual H(1)/5-HT(2A) activity and appropriate developability profiles. These compounds exhibited efficacy as hypnotic agents in a rat telemetric sleep model with minimal effective doses in the range 3-10 mg/kg po.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Antagonistas de los Receptores Histamínicos H1/síntesis química , Hipnóticos y Sedantes/síntesis química , Receptor de Serotonina 5-HT2A/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2/síntesis química , Sueño/efectos de los fármacos , Compuestos de Espiro/síntesis química , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Línea Celular , Corteza Cerebral/metabolismo , Cricetinae , Cricetulus , Compuestos Heterocíclicos de 4 o más Anillos/química , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Humanos , Hipnóticos y Sedantes/química , Hipnóticos y Sedantes/farmacología , Masculino , Microsomas Hepáticos/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Antagonistas del Receptor de Serotonina 5-HT2/química , Antagonistas del Receptor de Serotonina 5-HT2/farmacología , Trastornos del Sueño-Vigilia/tratamiento farmacológico , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti-Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by "aggrecanases". Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Zn-chelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Endopeptidasas/química , Inhibidores de Proteasas/química , Agrecanos/metabolismo , Secuencia de Aminoácidos , Antiinflamatorios no Esteroideos/farmacología , Artritis/tratamiento farmacológico , Endopeptidasas/metabolismo , Humanos , Datos de Secuencia Molecular , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , Alineación de Secuencia , Relación Estructura-ActividadRESUMEN
The synthesis of a series of carbazole derivatives and their SAR at the NPY Y1 receptor is described. Modulation of physicochemical properties by appropriate decoration led to the identification of a high-affinity NPY Y1 antagonist that shows high brain penetration and modest oral bioavailability.