RESUMEN
Ozanimod, recently approved for treating relapsing multiple sclerosis, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed K Mapp, V max, and intrinsic clearance (Clint) for CC112273 formation to be 4.8 µM, 50.3 pmol/min/mg protein, and 12 µl/min/mg, respectively, whereas Michaelis-Menten constant (K M) with human recombinant MAO B was 1.1 µM. Studies with liver mitochondrial fractions from preclinical species led to K Mapp, V max, and Clint estimates of 3.0, 35, and 33 µM, 80.6, 114, 37.3 pmol/min/mg, and 27.2, 3.25, and 1.14 µl/min/mg in monkey, rat, and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the K M Comparison of Clint estimates revealed monkey to be â¼2-fold more efficient and the mouse and rat to be 11- and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B-mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity toward catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that although both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the α-carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273. SIGNIFICANCE STATEMENT: This study evaluates the enzymology and the species differences of the major circulating metabolite of ozanimod, CC112273. Additionally, the study also explores the influence of stereochemistry on MAO B-catalyzed reactions. The study is of significance to the DMD readers given that this oxidation is catalyzed by a non-cytochrome P450 enzyme, and that marked species difference and notable stereospecificity was observed in MAO B-catalyzed biotransformation when the indaneamine enantiomers were used as substrates.
Asunto(s)
Indanos/farmacocinética , Monoaminooxidasa/metabolismo , Oxadiazoles/farmacocinética , Animales , Biotransformación , Desaminación , Evaluación Preclínica de Medicamentos , Haplorrinos , Humanos , Indanos/sangre , Tasa de Depuración Metabólica , Ratones , Mitocondrias Hepáticas/metabolismo , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Oxadiazoles/sangre , Oxidación-Reducción , Ratas , Especificidad de la Especie , Moduladores de los Receptores de fosfatos y esfingosina 1/sangre , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacocinética , EstereoisomerismoRESUMEN
Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.
Asunto(s)
Oxadiazoles/química , Receptores de Ácido Retinoico/agonistas , Administración Oral , Animales , Perros , Evaluación Preclínica de Medicamentos , Semivida , Locomoción/efectos de los fármacos , Células de Riñón Canino Madin Darby , Proyección Neuronal/efectos de los fármacos , Traumatismos del Nervio Óptico/tratamiento farmacológico , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Ratas , Receptores de Ácido Retinoico/metabolismo , Relación Estructura-ActividadRESUMEN
INTRODUCTION: The aim of the study was to clarify the dose response for inhibition of catechol-O-methyltransferase (COMT) by opicapone, a third generation COMT inhibitor, after acute and repeated administration to the cynomolgus monkey with pharmacokinetic evaluation at the higher dose. METHODS: Three cynomolgus monkeys were used in the study. In the first experiment, COMT inhibition was evaluated over 24â¯h after the first and at 24â¯h after the last of 14 daily oral administrations of vehicle, 1, 10 and 100â¯mg/kg opicapone using a crossover design. In the second experiment, the effect of the maximally effective dose, 100â¯mg/kg, was retested under the same conditions with additional monitoring of plasma opicapone levels to explore the relationship between pharmacokinetics and pharmacodynamics. RESULTS: Opicapone dose-dependently inhibited COMT activity, significantly so at 10 and 100â¯mg/kg. Maximal inhibition was 13.1%, 76.4% and 93.2% at 1, 10 and 100â¯mg/kg respectively, and COMT remained significantly inhibited at 24â¯h after 10 and 100â¯mg/kg (42.6% and 60.2% respectively). Following repeated administration of opicapone residual COMT inhibition at 24â¯h was 15-25% greater at all doses. In contrast to its pharmacodynamic effect, opicapone was rapidly absorbed and eliminated, with no accumulation in plasma following repeated administration. CONCLUSION: Opicapone showed sustained and dose-dependent COMT inhibition despite being rapidly eliminated from plasma and with no evidence for accumulation in plasma after 14 days administration. Opicapone fills the unmet need for a compound with sustained COMT inhibition which will improve levodopa bioavailability in patients with Parkinson's disease.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/administración & dosificación , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Catecol O-Metiltransferasa/metabolismo , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Femenino , Macaca fascicularis , Distribución Aleatoria , Factores de TiempoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder that has a higher prevalence and incidence in people older than 60 years. The need for improved AD therapies is unmet as the current therapies are symptomatic with modest efficacy. Partial agonists of the 5-HT4 receptor (5-HT4R) offer both symptomatic and disease-modifying treatments as they shift amyloid-precursor-protein (APP) processing from the amyloidogenic pathway to the nonamyloidogenic pathway by activating the α-secretase enzyme. In addition, they also offer symptomatic treatment by increasing levels of the neurotransmitter acetylcholine in the brain. Because of this fascinating dual mechanism of action, several chemical scaffolds having 5-HT4R pharmacophores were designed and evaluated. Most of the synthesized compounds showed potent in vitro affinities and in vivo efficacies. Upon analysis of focused structure-activity relationships, compound 4o was identified as a potent 5-HT4R partial agonist with favorable ADME properties and good in vivo efficacy. GR-125487, a selective 5-HT4R antagonist, attenuated the activity of compound 4o in the novel-object-recognition-test cognition model.
Asunto(s)
Amidas/química , Oxadiazoles/química , Oxadiazoles/farmacología , Receptores de Serotonina 5-HT4/metabolismo , Agonistas del Receptor de Serotonina 5-HT4/química , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Animales , Técnicas de Química Sintética , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Ratas , Ratas Wistar , Agonistas del Receptor de Serotonina 5-HT4/farmacocinética , Relación Estructura-ActividadRESUMEN
The toxicity of avagacestat, a sulfonamide-based gamma (γ)-secretase inhibitor that was in development as a treatment for Alzheimer's disease, was evaluated in a comprehensive nonclinical toxicology program that included 6-month and 1-year repeat-dose toxicity studies in rats and dogs, respectively. There was a spectrum of mechanism-based changes attributed to inhibition of Notch signaling that regulates the differentiation and proliferation of cells throughout development and in adult tissues. In both rats and dogs, ovarian follicular degeneration and atrophy and a low incidence of granulosa cell hyperplasia and benign granulosa-thecal cell tumors were observed. Gastrointestinal (GI) findings, including goblet cell metaplasia, dilatation of intestinal crypts/glands, mucosal epithelial necrosis and regeneration, and villous atrophy, were limited to dogs that had clinical evidence of GI toxicity. Other avagacestat-related findings attributed to interference with Notch signaling included decreases in peripheral lymphocytes (T and/or B cells) and lymphoid depletion in lymph nodes and the spleen in both species, as well as epiphyseal cartilage and trabecular bone changes in rats. Pharmacologically mediated decreases in brain and cerebrospinal fluid levels of ß-amyloid (Aß) peptides Aß40 and Aß42 and decreased expression of white blood cell mRNA levels of the Notch-regulated gene hairy and enhancer of split-1 confirmed target engagement at all doses. Reductions in brain Aß peptide levels (22 to 34%) in dogs after 1 year at exposures up to the no-observed-effect level for GI toxicity of 1.1× the human plasma exposure, and reversible GI changes at a 3.2× multiple, indicated that a sustained pharmacodynamic effect was attained at exposures without dose-limiting toxicity.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Tracto Gastrointestinal/efectos de los fármacos , Oxadiazoles/toxicidad , Receptores Notch/antagonistas & inhibidores , Sulfonamidas/toxicidad , Administración Oral , Péptidos beta-Amiloides/metabolismo , Animales , Área Bajo la Curva , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Perros , Evaluación Preclínica de Medicamentos , Femenino , Recuento de Linfocitos , Masculino , Oxadiazoles/farmacocinética , Ratas Sprague-Dawley , Factores Sexuales , Sulfonamidas/farmacocinética , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Pruebas de ToxicidadRESUMEN
Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor that emerged to fulfil the need of a safer and more efficacious COMT inhibitor. The present study was carried out in order to assess and compare the pharmacokinetics and pharmacodynamics (COMT inhibition) of opicapone after single and multiple oral administrations (30 mg/kg) to Wistar rats. For this purpose, at predefined time points up to 72 h post-dosing, blood, liver and kidneys were collected and, then, the concentrations of opicapone and its active metabolite (BIA 9-1079) were determined in plasma and in liver and kidney tissues, as well as the erythrocyte, liver and kidney COMT activity. No systemic, renal or hepatic accumulation of opicapone was observed following repeated administration. Furthermore, the tissue-systemic exposure relationships to opicapone suggested a low drug exposure in the liver and kidneys. After single-dosing, COMT inhibition profiles were reasonably comparable in all the studied matrices; although similar results were found after multiple-dosing, a higher degree of inhibition was observed, indicating a continuous peripheral COMT inhibition when opicapone is administered once-daily. Despite having a short elimination half-life (≤2.94 h), opicapone showed a strong and long-lasting COMT inhibition in both studies, since more than 50% of the COMT activity was still inhibited at 24 h post-dosing.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa/farmacología , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Oxadiazoles/farmacología , Oxadiazoles/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa/sangre , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Eritrocitos/efectos de los fármacos , Eritrocitos/enzimología , Riñón/efectos de los fármacos , Riñón/enzimología , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Oxadiazoles/sangre , Ratas WistarRESUMEN
A lead compound A was identified previously as an stearoyl coenzyme A desaturase (SCD) inhibitor during research on potential treatments for obesity. This compound showed high SCD1 binding affinity, but a poor pharmacokinetic (PK) profile and limited chemical accessibility, making it suboptimal for use in anticancer research. To identify potent SCD1 inhibitors with more promising PK profiles, we newly designed a series of 'non-spiro' 4, 4-disubstituted piperidine derivatives based on molecular modeling studies. As a result, we discovered compound 1a, which retained moderate SCD1 binding affinity. Optimization around 1a was accelerated by analyzing Hansch-Fujita and Hammett constants to obtain 4-phenyl-4-(trifluoromethyl)piperidine derivative 1n. Fine-tuning of the azole moiety of 1n led to compound 1o (T-3764518), which retained nanomolar affinity and exhibited an excellent PK profile. Reflecting the good potency and PK profile, orally administrated compound 1o showed significant pharmacodynamic (PD) marker reduction (at 0.3mg/kg, bid) in HCT116 mouse xenograft model and tumor growth suppression (at 1mg/kg, bid) in 786-O mouse xenograft model. In conclusion, we identified a new series of SCD1 inhibitors, represented by compound 1o, which represents a promising new chemical tool suitable for the study of SCD1 biology as well as the potential development of novel anticancer therapies.
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Antineoplásicos/química , Inhibidores Enzimáticos/síntesis química , Oxadiazoles/síntesis química , Piridazinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Células HCT116 , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Microsomas Hepáticos/metabolismo , Oxadiazoles/farmacocinética , Oxadiazoles/uso terapéutico , Oxadiazoles/toxicidad , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacología , Unión Proteica , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Piridazinas/toxicidad , Compuestos de Espiro/química , Estearoil-CoA Desaturasa/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethylâ (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.
Asunto(s)
Inhibidores de Integrasa VIH/química , Oxadiazoles/química , Profármacos/química , Pirimidinonas/química , Pirrolidinonas/química , Acetales/química , Animales , Área Bajo la Curva , Carbonatos/química , Perros , Evaluación Preclínica de Medicamentos , Integrasa de VIH/química , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacocinética , VIH-1/enzimología , Semivida , Hepatocitos/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Masculino , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Profármacos/síntesis química , Profármacos/farmacocinética , Pirimidinonas/síntesis química , Pirimidinonas/farmacocinética , Curva ROC , Raltegravir Potásico , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.
Asunto(s)
Corteza Cerebral/enzimología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/efectos de los fármacos , Nootrópicos/farmacología , Oxadiazoles/farmacología , Inhibidores de Fosfodiesterasa 4/efectos adversos , Inhibidores de Fosfodiesterasa 4/farmacología , Tiazoles/farmacología , Aminopiridinas/farmacología , Animales , Ansiolíticos/efectos adversos , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Conducta Animal/efectos de los fármacos , Benzamidas/farmacología , Callithrix , Corteza Cerebral/efectos de los fármacos , Ciclopropanos/farmacología , Evaluación Preclínica de Medicamentos , Hurones , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Isoenzimas/antagonistas & inhibidores , Macaca fascicularis , Masculino , Nootrópicos/efectos adversos , Nootrópicos/farmacocinética , Nootrópicos/uso terapéutico , Oxadiazoles/efectos adversos , Oxadiazoles/farmacocinética , Oxadiazoles/uso terapéutico , Inhibidores de Fosfodiesterasa 4/farmacocinética , Pica/tratamiento farmacológico , Ratas , Rolipram/farmacología , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Tiazoles/uso terapéuticoRESUMEN
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.
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Oxadiazoles/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Animales , Sitios de Unión , Sistema Nervioso Central/diagnóstico por imagen , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Marcaje Isotópico , Masculino , Microsomas/metabolismo , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Piridinas/síntesis química , Piridinas/farmacocinética , Cintigrafía , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-ActividadRESUMEN
The manuscript reports an identification of a highly potent, orally bioavailable hepatitis C virus entry inhibitor through optimization of a previously reported class of molecules (1) that were not stable in the rat plasma. Compound 39 (ITX 4520) exhibited an excellent PK profile in both rats and dogs with good oral exposure, half-life and oral bioavailability. The compound is also well-tolerated in the preliminary in vivo toxicity studies and has been selected as a pre-clinical candidate for our HCV clinical pipeline.
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Antivirales/química , Carbazoles/química , Hepacivirus/metabolismo , Oxadiazoles/química , Internalización del Virus/efectos de los fármacos , Administración Oral , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Disponibilidad Biológica , Carbazoles/síntesis química , Carbazoles/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Microsomas/metabolismo , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Molecules that induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein hold great therapeutic potential for the treatment of many genetic disorders. Two such read-through compounds, RTC13 and RTC14, were recently identified by a luciferase-independent high-throughput screening assay and were shown to have potential therapeutic functions in the treatment of nonsense mutations in the ATM and the dystrophin genes. We have now tested the ability of RTC13 and RTC14 to restore dystrophin expression into skeletal muscles of the mdx mouse model for Duchenne muscular dystrophy (DMD). Direct intramuscular injection of compound RTC14 did not result in significant read-through activity in vivo and demonstrated the levels of dystrophin protein similar to those detected using gentamicin. In contrast, significant higher amounts of dystrophin were detected after intramuscular injection of RTC13. When administered systemically, RTC13 was shown to partially restore dystrophin protein in different muscle groups, including diaphragm and heart, and improved muscle function. An increase in muscle strength was detected in all treated animals and was accompanied by a significant decrease in creatine kinase levels. These studies establish the therapeutic potential of RTC13 in vivo and advance this newly identified compound into preclinical application for DMD.
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Distrofina/genética , Furanos/farmacología , Músculo Esquelético/fisiopatología , Distrofia Muscular de Duchenne/tratamiento farmacológico , Fenoles/farmacología , Bases de Schiff/farmacología , Tiazolidinas/farmacología , Transcripción Genética/efectos de los fármacos , Animales , Codón sin Sentido , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Distrofina/metabolismo , Furanos/administración & dosificación , Furanos/farmacocinética , Gentamicinas/administración & dosificación , Gentamicinas/farmacología , Inyecciones Intramusculares , Inyecciones Intraperitoneales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatología , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Fenoles/administración & dosificación , Inhibidores de la Síntesis de la Proteína/administración & dosificación , Inhibidores de la Síntesis de la Proteína/farmacología , Sistemas de Lectura , Bases de Schiff/administración & dosificación , Tiazolidinas/administración & dosificación , Tiazolidinas/farmacocinéticaRESUMEN
A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.
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Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Hipoglucemiantes/síntesis química , Oxadiazoles/síntesis química , Animales , Diabetes Mellitus/tratamiento farmacológico , Diacilglicerol O-Acetiltransferasa/metabolismo , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Semivida , Ensayos Analíticos de Alto Rendimiento , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Ligandos , Ratones , Obesidad/tratamiento farmacológico , Oxadiazoles/farmacocinética , Relación Estructura-Actividad Cuantitativa , RatasRESUMEN
Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of ß- or γ-secretase, key enzymes for the production of amyloid ß (Aß), may be viable mechanisms for the treatment of AD. For the discovery of γ-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of Aß species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for Aß lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF Aß across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain Aßx-42 and CSF Aßx-40 in the 129/SVE mouse is indicative of that for human CSF Aß. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of Aß data are established.
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Alanina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Azepinas/farmacología , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Oxadiazoles/farmacología , Sulfonamidas/farmacología , Alanina/sangre , Alanina/farmacocinética , Alanina/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Azepinas/sangre , Azepinas/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/sangre , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Ratones de la Cepa 129 , Ratones Transgénicos , Modelos Animales , Oxadiazoles/sangre , Oxadiazoles/farmacocinética , Bibliotecas de Moléculas Pequeñas , Sulfonamidas/sangre , Sulfonamidas/farmacocinéticaRESUMEN
S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.
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Enfermedades Autoinmunes/tratamiento farmacológico , Butiratos/síntesis química , Butiratos/farmacología , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Indoles/síntesis química , Indoles/farmacología , Linfocitos/metabolismo , Proteínas del Tejido Nervioso/agonistas , Oxadiazoles/síntesis química , Oxadiazoles/farmacología , Proteínas de Unión al ARN/agonistas , Animales , Butiratos/farmacocinética , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Haplorrinos , Ensayos Analíticos de Alto Rendimiento , Humanos , Inmunosupresores/farmacocinética , Indoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/química , Oxadiazoles/farmacocinética , Proteínas de Unión al ARN/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
Biaryl cyclohexene carboxylic acids were discovered as full and potent niacin receptor (GPR109A) agonists. Compound 1e (MK-6892) displayed excellent receptor activity, good PK across species, remarkably clean off-target profiles, good ancillary pharmacology, and superior therapeutic window over niacin regarding the FFA reduction versus vasodilation in rats and dogs.
Asunto(s)
Ácidos Carboxílicos/farmacología , Ácidos Ciclohexanocarboxílicos/farmacología , Ciclohexenos/química , Descubrimiento de Drogas , Oxadiazoles/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Área Bajo la Curva , Unión Competitiva , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Perros , Evaluación Preclínica de Medicamentos , Ácidos Grasos no Esterificados/sangre , Humanos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Químicos , Estructura Molecular , Oxadiazoles/química , Oxadiazoles/farmacocinética , Ratas , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Relación Estructura-Actividad , Vasodilatación/efectos de los fármacosRESUMEN
The CB2 receptor is an attractive therapeutic target for analgesic and anti-inflammatory agents. Herein we describe the discovery of a novel class of oxadiazole derivatives from which potent and selective CB2 agonist leads were developed. Initial hit 7 was identified from a cannabinoid target-biased library generated by virtual screening of sample collections using a pharmacophore model in combination with a series of physicochemical filters. 7 was demonstrated to be a selective CB2 agonist (CB2 EC50 = 93 nM, Emax = 98%, CB1 EC50 > 10 microM). However, this compound exhibited poor solubility and relatively high clearance in rat, resulting in low oral bioavailability. In this paper, we report detailed SAR studies on 7 en route toward improving potency, physicochemical properties, and solubility. This effort resulted in identification of 63 that is a potent and selective agonist at CB2 (EC50 = 2 nM, Emax = 110%) with excellent pharmacokinetic properties.