RESUMEN
Proprotein convertase substilisin-like/kexin type 9 (PCSK9) is a serine protease involved in a protein-protein interaction with the low-density lipoprotein (LDL) receptor that has both human genetic and clinical validation. Blocking this protein-protein interaction prevents LDL receptor degradation and thereby decreases LDL cholesterol levels. Our pursuit of small-molecule direct binders for this difficult to drug PPI target utilized affinity selection/mass spectrometry, which identified one confirmed hit compound. An X-ray crystal structure revealed that this compound was binding in an unprecedented allosteric pocket located between the catalytic and C-terminal domain. Optimization of this initial hit, using two distinct strategies, led to compounds with high binding affinity to PCSK9. Direct target engagement was demonstrated in the cell lysate with a cellular thermal shift assay. Finally, ligand-induced protein degradation was shown with a proteasome recruiting tag attached to the high-affinity allosteric ligand for PCSK9.
Asunto(s)
Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Proproteína Convertasa 9/metabolismo , Proteolisis/efectos de los fármacos , Inhibidores de Serina Proteinasa/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Humanos , Ligandos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/química , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
The use of nicotinic acid to treat dyslipidemia is limited by induction of a "flushing" response, mediated in part by the interaction of prostaglandin D(2) (PGD(2)) with its G-protein coupled receptor, DP1 (Ptgdr). The impact of DP1 blockade (genetic or pharmacologic) was assessed in experimental murine models of atherosclerosis. In Ptgdr(-/-)ApoE(-/-) mice versus ApoE(-/-) mice, both fed a high-fat diet, aortic cholesterol content was modestly higher (1.3- to 1.5-fold, P < 0.05) in Ptgdr(-/-)ApoE(-/-) mice at 16 and 24 weeks of age, but not at 32 weeks. In multiple ApoE(-/-) mouse studies, a DP1-specific antagonist, L-655, generally had a neutral to beneficial effect on aortic lipids in the presence or absence of nicotinic acid treatment. In a separate study, a modest increase in some atherosclerotic measures was observed with L-655 treatment in Ldlr(-/-) mice fed a high-fat diet for 8 weeks; however, this effect was not sustained for 16 or 24 weeks. In the same study, treatment with nicotinic acid alone generally decreased plasma and/or aortic lipids, and addition of L-655 did not negate those beneficial effects. These studies demonstrate that inhibition of DP1, with or without nicotinic acid treatment, does not lead to consistent or sustained effects on plaque burden in mouse atherosclerotic models.
Asunto(s)
Técnicas de Silenciamiento del Gen , Niacina/farmacología , Placa Aterosclerótica/tratamiento farmacológico , Placa Aterosclerótica/metabolismo , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/genética , Receptores de Prostaglandina/antagonistas & inhibidores , Receptores de Prostaglandina/genética , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Apolipoproteínas E/deficiencia , Colesterol/metabolismo , Interacciones Farmacológicas , Determinación de Punto Final , Femenino , Humanos , Masculino , Ratones , Niacina/uso terapéutico , Placa Aterosclerótica/genética , Receptores Inmunológicos/deficiencia , Receptores de LDL/deficiencia , Receptores de Prostaglandina/deficiencia , Receptores de Tromboxano A2 y Prostaglandina H2/metabolismoRESUMEN
The function of a particular protein is dependent upon its localization and milieu. The ability to track the "fate" of a protein is a valuable tool to elucidate its function. We present the use of HaloTag technology to study the localization and fate of human Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9).The role of PCSK9 in the regulation of circulating low density lipoprotein-cholesterol (LDL-c) levels is ascribed to binding of circulating PCSK9 to the LDL receptor (LDLR) and subsequent lysosomal degradation of LDLR. However, hints in the literature indicate that intracellular PCSK9 may act on the LDLR, possibly during processing of newly synthesized protein. To address this question, the source and fate of intracellular PCSK9 requires further investigation.We applied HaloTag technology to distinguish the source of intracellular PCSK9 and showed that newly synthesized intracellular PCSK9 has unique localization from the PCSK9 after re-uptake. This suggests different functions of PCSK9 while interacting with the LDLR.
RESUMEN
Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor expressed primarily in the hypothalamus which plays a role in the onset of both diabetes and obesity. We report herein our progress made towards identifying a potent, selective bombesin receptor subtype-3 (BRS-3) agonist related to the previously described MK-7725(1) Chobanian et al. (2012) that would prevent atropisomerization through the increase of steric bulk at the C-2 position. This would thereby make clinical development of this class of compounds more cost effective by inhibiting racemization which can occur over long periods of time at room/elevated temperature.
Asunto(s)
Benzodiazepinas/química , Diseño de Fármacos , Receptores de Bombesina/agonistas , Sulfonamidas/química , Sulfonamidas/síntesis química , Animales , Humanos , Ratones , Unión Proteica , Ratas , Receptores de Bombesina/metabolismo , Estereoisomerismo , Sulfonamidas/farmacocinética , TemperaturaRESUMEN
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a promising therapeutic target for treating coronary heart disease. We report a novel antibody 1B20 that binds to PCSK9 with sub-nanomolar affinity and antagonizes PCSK9 function in-vitro. In CETP/LDLR-hemi mice two successive doses of 1B20, administered 14 days apart at 3 or 10 mpk, induced dose dependent reductions in LDL-cholesterol (≥ 25% for 7-14 days) that correlated well with the extent of PCSK9 occupancy by the antibody. In addition, 1B20 induces increases in total plasma antibody-bound PCSK9 levels and decreases in liver mRNA levels of SREBP-regulated genes PCSK9 and LDLR, with a time course that parallels decreases in plasma LDL-cholesterol (LDL-C). Consistent with this observation in mice, in statin-responsive human primary hepatocytes, 1B20 lowers PCSK9 and LDLR mRNA levels and raises serum steady-state levels of antibody-bound PCSK9. In addition, mRNA levels of several SREBP regulated genes involved in cholesterol and fatty-acid synthesis including ACSS2, FDPS, IDI1, MVD, HMGCR, and CYP51A1 were decreased significantly with antibody treatment of primary human hepatocytes. In rhesus monkeys, subcutaneous (SC) dosing of 1B20 dose-dependently induces robust LDL-C lowering (maximal ~70%), which is correlated with increases in target engagement and total antibody-bound PCSK9 levels. Importantly, a combination of 1B20 and Simvastatin in dyslipidemic rhesus monkeys reduced LDL-C more than either agent alone, consistent with a mechanism of action that predicts additive effects of anti-PCSK9 agents with statins. Our results suggest that antibodies targeting PCSK9 could provide patients powerful LDL lowering efficacy on top of statins, and lower cardiovascular risk.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/efectos de los fármacos , Inmunización Pasiva , Síndrome Metabólico/terapia , Proproteína Convertasas/antagonistas & inhibidores , Proproteína Convertasas/inmunología , Serina Endopeptidasas/inmunología , Simvastatina/uso terapéutico , Proteínas de Unión a los Elementos Reguladores de Esteroles/fisiología , Animales , Anticuerpos Monoclonales/farmacología , Afinidad de Anticuerpos , Anticolesterolemiantes/administración & dosificación , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Perfilación de la Expresión Génica , Células Hep G2/efectos de los fármacos , Células Hep G2/metabolismo , Hepatocitos/metabolismo , Humanos , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Macaca mulatta , Síndrome Metabólico/tratamiento farmacológico , Síndrome Metabólico/genética , Ratones , Ratones Transgénicos , Proproteína Convertasa 9 , Proproteína Convertasas/biosíntesis , Proproteína Convertasas/genética , ARN Mensajero/metabolismo , Receptores de LDL/biosíntesis , Receptores de LDL/genética , Proteínas Recombinantes/metabolismo , Serina Endopeptidasas/biosíntesis , Serina Endopeptidasas/genética , Simvastatina/administración & dosificaciónRESUMEN
Extensive structure-activity relationship studies of a series derived from atropisomer 1, a previously described chiral benzodiazepine sulfonamide series, led to a potent, brain penetrant and selective compound with excellent preclinical pharmacokinetic across species. We also describe the utilization of a high throughput mouse pharmacodynamic assay which allowed for expedient assessment of pharmacokinetic and brain distribution.
RESUMEN
Pharmacologic inhibition of the cannabinoid-1 receptor (CB1R) in rodent models leads to weight loss and time-dependent changes in energy balance. This study evaluated the effects of CB1R inhibition on weight loss, energy expenditure (EE), and food intake (FI) in an obese canine model following 4 weeks of treatment. Eighteen maintenance-fed obese beagles were evenly and randomly allocated to a CB1R inverse agonist (AM251) (2 mg/kg), a 70% food-restricted (FR) diet, or a control group (C). Evaluations included body weight and composition (dual-energy x-ray absorptiometry scan), EE (doubly labeled water), and FI. Change in body mass at week 4 was significantly greater (P < .050) in the AM251 (-1476.7 g) and FR groups (-1100.0 g) than in the C group (-228.3 g). Food intake was decreased from week 2 onward in the FR and AM251 groups (P < .05). Absolute and lean mass-adjusted EEs were decreased only in the FR group (P < .01); EE in the AM251 group was greater (P < .05) than that in the FR group. Pharmacologic inhibition of CB1R in a canine model led to sustained effects on FI and EE. Weight loss was greater with AM251 than could be accounted for by food restriction (â¼25%), an effect likely mediated by the EE response to CB1R inhibition.
Asunto(s)
Metabolismo Energético/fisiología , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Pérdida de Peso/efectos de los fármacos , Absorciometría de Fotón , Animales , Modelos Animales de Enfermedad , Perros , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Prueba de Tolerancia a la Glucosa , Distribución Aleatoria , Receptor Cannabinoide CB1/metabolismo , Pérdida de Peso/fisiologíaRESUMEN
In an attempt to understand the applicability of various animal models to dyslipidemia in humans and to identify improved preclinical models for target discovery and validation for dyslipidemia, we measured comprehensive plasma lipid profiles in 24 models. These included five mouse strains, six other nonprimate species, and four nonhuman primate (NHP) species, and both healthy animals and animals with metabolic disorders. Dyslipidemic humans were assessed by the same measures. Plasma lipoprotein profiles, eight major plasma lipid fractions, and FA compositions within these lipid fractions were compared both qualitatively and quantitatively across the species. Given the importance of statins in decreasing plasma low-density lipoprotein cholesterol for treatment of dyslipidemia in humans, the responses of these measures to simvastatin treatment were also assessed for each species and compared with dyslipidemic humans. NHPs, followed by dog, were the models that demonstrated closest overall match to dyslipidemic humans. For the subset of the dyslipidemic population with high plasma triglyceride levels, the data also pointed to hamster and db/db mouse as representative models for practical use in target validation. Most traditional models, including rabbit, Zucker diabetic fatty rat, and the majority of mouse models, did not demonstrate overall similarity to dyslipidemic humans in this study.
Asunto(s)
Modelos Animales de Enfermedad , Dislipidemias/sangre , Lípidos/sangre , Animales , Cricetinae , Perros , Dislipidemias/tratamiento farmacológico , Ácidos Grasos/sangre , Humanos , Ratones , Primates , Simvastatina/uso terapéutico , Triglicéridos/sangreRESUMEN
High-density lipoprotein (HDL)-targeting therapies, including reconstituted HDL (rHDL), are attractive agents for treating dyslipidemia and atherosclerosis, as they may increase HDL levels and enhance therapeutic activities associated with HDL, including reverse cholesterol transport (RCT). Using CSL-111, a rHDL consisting of native human apolipoprotein AI (hApoAI) and phospholipids, we characterized the acute effects of rHDL administration in C57Bl/6 mice to (i) further our understanding of the mechanism of action of rHDL, and (ii) evaluate the usefulness of the mouse as a preclinical model for HDL-targeting therapies. After a single injection of CSL-111, there was a dose- and time-dependent increase of hApoAI, human pre-ß HDL, total cholesterol, and triglycerides in serum, consistent with the effects of CSL-111 in humans. However, unlike in humans, there was no measurable increase in cholesteryl esters. Evaluated ex vivo, the ATP binding cassette A1 (ABCA1)- and scavenger receptor type BI (SR-BI)-dependent cholesterol efflux capacity of serum from CSL-111-treated mice was increased compared with serum from vehicle-treated animals. Fractionation by size exclusion chromatography of lipoproteins in serum from treated mice revealed hApoAI in particles the size of endogenous HDL and slightly larger, cholesterol-enriched particles of all sizes, including sizes distinct from endogenous HDL or CSL-111 itself, and triglyceride-enriched particles the size of very-low-density lipoprotein (VLDL). These results suggest that in mouse blood CSL-111 is remodeled and generates enhanced cholesterol efflux capacity which increases mobilization of free cholesterol from peripheral tissues. Our findings complement the previous reports on CSL-111 in human participants and provide data with which to evaluate the potential utility of mouse models in mechanistic studies of HDL-targeting therapies.
Asunto(s)
HDL-Colesterol/farmacología , Lípidos/sangre , Animales , Factor de Transcripción COUP II/genética , Factor de Transcripción COUP II/metabolismo , Línea Celular , Colesterol/metabolismo , HDL-Colesterol/administración & dosificación , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Lipoproteínas de Alta Densidad Pre-beta/metabolismo , Inyecciones Intravenosas , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , FosfatidilcolinasRESUMEN
A series of six-membered heterocycle carboxamides were synthesized and evaluated as cholecystokinin 1 receptor (CCK1R) agonists. A pyrimidine core proved to be the best heterocycle, and SAR studies resulted in the discovery of analog 5, a potent and structurally diverse CCK1R agonist.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Receptor de Colecistoquinina A/agonistas , Amidas/química , Animales , Células Cultivadas , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Estructura Molecular , Unión Proteica/efectos de los fármacos , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
We report the discovery of piperazine urea based compound 1, a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist. Compound 1 shows anti-obesity efficacy without potentiating erectile activity in the rodent models.
Asunto(s)
Piperazinas/química , Receptor de Melanocortina Tipo 4/agonistas , Urea/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Ingestión de Alimentos/efectos de los fármacos , Haplorrinos , Ratones , Obesidad/tratamiento farmacológico , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/uso terapéuticoRESUMEN
Emerging evidence suggests apolipoprotein B (apoB) and apolipoprotein AI (apoAI) are strong risk predictors for atherosclerosis. Non-human primates (NHP), including rhesus monkeys, cynomolgus monkeys, and African green monkeys, are important preclinical species for studying dyslipidemia and atherosclerosis as they more closely resemble humans in lipid metabolism and disease physiology compared to lower species such as rodents. However, no commercial assays are currently available for measuring apoB and apoAI in NHP. We therefore evaluated analytical methods for routinely measuring apoB and apoAI in our NHP dyslipidemia and atherosclerosis research. Since NHP apoB and apoAI sequences are likely highly similar to human, we focused on the clinically validated and widely utilized human apoB and apoAI immunoturbidity assays. We carried out technical validation of these assays with NHP samples and leveraged orthogonal technical platforms including mass spectrometry, independent ELISA assay, and absolute quantitation via SDS-PAGE for further characterization. Analysis of purified lipoproteins demonstrated that the immunoturbidity assays detect NHP apoAI and apoB, with good dilution linearity and spike recovery from NHP plasma. Orthogonal studies showed apoAI correlated with protein concentration and apoB levels correlated with LC/MS and an independent ELISA. NHP samples from a drug treatment study were analyzed with the immunoturbidity assays and levels of apoB and apoAI fit our understanding of biology and expectations from literature. These studies serve as important technical and biological validation of the immunoturbidity assays for NHP samples, and demonstrate that these assays provide a high-throughput, fully automated analytical platform for NHP samples. Our studies pave the way for future translational research in NHP for developing therapies for treating dyslipidemia and atherosclerosis.
Asunto(s)
Apolipoproteína A-I/sangre , Apolipoproteínas B/sangre , Aterosclerosis/sangre , Dislipidemias/sangre , Inmunoensayo , Nefelometría y Turbidimetría , Animales , Aterosclerosis/diagnóstico , Aterosclerosis/tratamiento farmacológico , Biomarcadores/sangre , Calibración , Modelos Animales de Enfermedad , Dislipidemias/diagnóstico , Dislipidemias/tratamiento farmacológico , Electroforesis en Gel de Poliacrilamida , Ensayo de Inmunoadsorción Enzimática , Haplorrinos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inmunoensayo/normas , Espectrometría de Masas , Nefelometría y Turbidimetría/normas , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Simvastatina/farmacologíaRESUMEN
Bombesin receptor subtype-3 (BRS-3) is an orphan G protein-coupled receptor implicated in the regulation of energy homeostasis. Here, we report the biologic effects of a highly optimized BRS-3 agonist, (2S)-1,1,1-trifluoro-2-[4-(1H-pyrazol-1-yl)phenyl]-3-(4-{[1-(trifluoromethyl)cyclopropyl]methyl}-1H-imidazol-2-yl)propan-2-ol (MK-5046). Single oral doses of MK-5046 inhibited 2-h and overnight food intake and increased fasting metabolic rate in wild-type but not Brs3 knockout mice. Upon dosing for 14 days, MK-5046 at 25 mg · kg(-1) · day(-1) reduced body weight of diet-induced obese mouse by 9% compared with vehicle-dosed controls. In mice, 50% brain receptor occupancy was achieved at a plasma concentration of 0.34 ± 0.23 µM. With chronic dosing, effects on metabolic rate, rather than food intake, seem to be the predominant mechanism for weight reduction by MK-5046. The compound also effectively reduced body weight in rats and caused modest increases in body temperature, heart rate, and blood pressure. These latter effects on temperature, heart rate, and blood pressure were transient in nature and desensitized with continued dosing. MK-5046 is the first BRS-3 agonist with properties suitable for use in larger mammals. In dogs, MK-5046 treatment produced statistically significant and persistent weight loss, which was initially accompanied by increases in body temperature and heart rate that abated with continued dosing. Our results demonstrate antiobesity efficacy for MK-5046 in rodents and dogs and further support BRS-3 agonism as a new approach to the treatment of obesity.
Asunto(s)
Fármacos Antiobesidad/farmacología , Imidazoles/farmacología , Pirazoles/farmacología , Receptores de Bombesina/agonistas , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Metabolismo Energético/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Receptores de Bombesina/análisisRESUMEN
We report herein the discovery of benzodiazepine sulfonamide-based bombesin receptor subtype 3 (BRS-3) agonists and their unusual chirality. Starting from a high-throughput screening lead, we prepared a series of BRS-3 agonists with improved potency and pharmacokinetic properties, of which compound 8a caused mechanism-based, dose-dependent food intake reduction and body weight loss after oral dosing in diet-induced obese mice. This effort also led to the discovery of a novel family of chiral molecules originated from the conformationally constrained seven-membered diazepine ring.
RESUMEN
We report an SAR study of MC4R analogs containing spiroindane heterocyclic privileged structures. Compound 26 with N-Me-1,2,4-triazole moiety possesses exceptional potency at MC4R and potent anti-obesity efficacy in a mouse model. However, the efficacy is not completely mediated through MC4R. Additional SAR studies led to the discovery of compound 32, which is more potent at MC4R. Compound 32 demonstrates MC4R mediated anti-obesity efficacy in rodent models.
Asunto(s)
Obesidad/tratamiento farmacológico , Receptor de Melanocortina Tipo 4/agonistas , Triazoles/farmacología , Animales , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Ratones , Ratones Noqueados , Estructura Molecular , Ratas , Receptor de Melanocortina Tipo 4/genética , Relación Estructura-Actividad , Triazoles/química , Triazoles/uso terapéuticoRESUMEN
Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (T(b)) is regulated in part by nutritional status, with a reduced T(b) during fasting. We report that fed Brs3 knockout mice have a lower T(b), which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased T(b), more so when the baseline T(b) was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the T(b) increase attenuated despite continued weight loss efficacy. The increase in T(b) was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a ß-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting T(b) reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, ß3-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted T(b) and the fasted, resting metabolic rates. The T(b) assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery.
Asunto(s)
Fármacos Antiobesidad/farmacología , Regulación de la Temperatura Corporal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Receptores de Bombesina/agonistas , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/fisiología , Metabolismo Energético/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Obesos , Obesidad/metabolismo , Obesidad/fisiopatología , Receptores de Bombesina/metabolismo , Pérdida de Peso/fisiologíaRESUMEN
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Asunto(s)
Amidas/química , Fármacos Antiobesidad/química , Obesidad/tratamiento farmacológico , Pirrolidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Compuestos de Espiro/química , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Peso Corporal/efectos de los fármacos , Humanos , Ratones , Ratones Noqueados , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/uso terapéutico , Relación Estructura-ActividadRESUMEN
Design, synthesis, and SAR of a series of 3H-spiro[isobenzofuran-1,4'-piperidine] based compounds as potent, selective and orally bioavailable melanocortin subtype-4 receptor (MC4R) agonists are disclosed.
Asunto(s)
Piperidinas/química , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Encéfalo/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Conformación Molecular , Piperidinas/síntesis química , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
Synthesis and structure-activity relationships of cannabinoid-1 receptor (CB1R) inverse agonists based on dihydro-pyrano[2,3-b] pyridine and tetrahydro-1,8-naphtyridine scaffolds are presented. Rat food intake and pharmacokinetic evaluation of 13g, 13i, 13k and 17a revealed these compounds to be highly efficacious orally active modulators of CB1R.
Asunto(s)
Naftiridinas/química , Piridinas/química , Receptor Cannabinoide CB1/agonistas , Pérdida de Peso/efectos de los fármacos , Administración Oral , Animales , Ingestión de Alimentos , Humanos , Naftiridinas/síntesis química , Naftiridinas/farmacología , Farmacocinética , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Cannabinoide CB1/efectos de los fármacos , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
This paper describes the discovery of N-[(4R)-6-(4-chlorophenyl)-7-(2,4-dichlorophenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl]-5-methyl-1H-pyrazole-3-carboxamide (MK-5596, 12c) as a novel cannabinoid-1 receptor (CB1R) inverse agonist for the treatment of obesity. Structure-activity relationship (SAR) studies of lead compound 3, which had off-target hERG (human ether-a-go-go related gene) inhibition activity, led to the identification of several compounds that not only had attenuated hERG inhibition activity but also were subject to glucuronidation in vitro providing the potential for multiple metabolic clearance pathways. Among them, pyrazole 12c was found to be a highly selective CB1R inverse agonist that reduced body weight and food intake in a DIO (diet-induced obese) rat model through a CB1R-mediated mechanism. Although 12c was a substrate of P-glycoprotein (P-gp) transporter, its high in vivo efficacy in rodents, good pharmacokinetic properties in preclinical species, good safety margins, and its potential for a balanced metabolism profile in man allowed for the further evaluation of this compound in the clinic.