RESUMEN
We report herein the identification of MK-4409, a potent and selective fatty acid amide hydrolase (FAAH) inhibitor. Starting from a high throughput screening (HTS) hit, medicinal chemistry efforts focused on optimizing of FAAH inhibition in vitro potency, improving the pharmacokinetic (PK) profile, and increasing in vivo efficacy in rodent inflammatory and neuropathic pain assays.
RESUMEN
The discovery of 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia is described. The initial hit class, spirooxindoles, was identified through affinity selection mass spectrometry (AS-MS) and optimized for PHD2 inhibition and optimal PK/PD profile (short-acting PHDi inhibitors). 1,3,8-Triazaspiro[4.5]decane-2,4-diones (spirohydantoins) were optimized as an advanced lead class derived from the original spiroindole hit. A new set of general conditions for C-N coupling, developed using a high-throughput experimentation (HTE) technique, enabled a full SAR analysis of the spirohydantoins. This rapid and directed SAR exploration has resulted in the first reported examples of hydantoin derivatives with good PK in preclinical species. Potassium channel off-target activity (hERG) was successfully eliminated through the systematic introduction of acidic functionality to the molecular structure. Undesired upregulation of alanine aminotransferese (ALT) liver enzymes was mitigated and a robust on-/off-target margin was achieved. Spirohydantoins represent a class of highly efficacious, short-acting PHD1-3 inhibitors causing a robust erythropoietin (EPO) upregulation in vivo in multiple preclinical species. This profile deems spirohydantoins as attractive short-acting PHDi inhibitors with the potential for treatment of anemia.
Asunto(s)
Anemia/tratamiento farmacológico , Compuestos Aza/síntesis química , Hidantoínas/síntesis química , Factor 1 Inducible por Hipoxia/metabolismo , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Animales , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Perros , Canal de Potasio ERG1 , Eritropoyetina/biosíntesis , Canales de Potasio Éter-A-Go-Go/metabolismo , Ensayos Analíticos de Alto Rendimiento , Humanos , Hidantoínas/farmacocinética , Hidantoínas/farmacología , Prolina Dioxigenasas del Factor Inducible por Hipoxia , Indoles/síntesis química , Indoles/farmacocinética , Indoles/farmacología , Hígado/efectos de los fármacos , Hígado/enzimología , Macaca mulatta , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Regulación hacia ArribaRESUMEN
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
We report the development and characterization of compound 22 (MK-5046), a potent, selective small molecule agonist of BRS-3 (bombesin receptor subtype-3). In pharmacological testing using diet-induced obese mice, compound 22 caused mechanism-based, dose-dependent reductions in food intake and body weight.
RESUMEN
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
Design, syntheses and structure-activity relationships of N-acetylated piperazine privileged structures containing MC4R agonist compounds were described. The most potent derivatives were low nM MC4R selective full agonists. Several compounds from the series had modest pharmacokinetic properties.
Asunto(s)
Ligandos , Receptor de Melanocortina Tipo 4/agonistas , Animales , Humanos , Piperazina , Piperazinas/síntesis química , Piperazinas/química , Piperazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptor de Melanocortina Tipo 4/metabolismo , 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
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
We report the design, synthesis and properties of spiroindane based compound 1, a potent, selective, orally bioavailable, non-peptide melanocortin subtype-4 receptor agonist. Compound 1 shows excellent erectogenic activity in the rodent models.
Asunto(s)
Disfunción Eréctil/tratamiento farmacológico , Indanos/química , Indanos/uso terapéutico , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Espiro/química , Compuestos de Espiro/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Perros , Haplorrinos , Humanos , Indanos/farmacocinética , Indanos/farmacología , Masculino , Ratones , Estructura Molecular , Unión Proteica , Ratas , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC(50)=18 nM, hBRS-3) and functional agonist activity (EC(50)=47 nM, 99% activation). After oral administration, compound 9 had sufficient exposure in diet induced obese mice to demonstrate efficacy in lowering food intake and body weight via BRS-3 activation.
Asunto(s)
Imidazoles/química , Imidazoles/uso terapéutico , Obesidad/tratamiento farmacológico , Receptores de Bombesina/agonistas , Receptores de Bombesina/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.
Asunto(s)
Descubrimiento de Drogas , Imidazoles/química , Imidazoles/farmacología , Receptores de Bombesina/agonistas , Animales , Disponibilidad Biológica , Humanos , Imidazoles/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.
Asunto(s)
Control de Insectos , Insecticidas , Siphonaptera , Garrapatas , Tejido Adiposo/metabolismo , Administración Oral , Animales , Gatos , Perros , Femenino , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/farmacocinética , Alcaloides Indólicos/farmacología , Indoles , Insecticidas/administración & dosificación , Insecticidas/síntesis química , Masculino , Ratones , Distribución TisularRESUMEN
Discovery of a series of tert-butyl pyrrolidine derived, potent and orally bioavailable melanocortin receptor subtype-4 (MC4R) selective modulators is disclosed.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Humanos , Estructura Molecular , Estereoisomerismo , Relación Estructura-Actividad , TelomerasaRESUMEN
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Asunto(s)
Anticonvulsivantes/farmacología , Benzodiazepinonas/farmacología , Epilepsia/tratamiento farmacológico , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Bloqueadores de los Canales de Sodio/farmacología , Animales , Anticonvulsivantes/síntesis química , Anticonvulsivantes/farmacocinética , Benzodiazepinonas/síntesis química , Benzodiazepinonas/farmacocinética , Electrofisiología , Electrochoque , Epilepsia/metabolismo , Canales de Potasio Éter-A-Go-Go/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Humanos , Ratones , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacocinéticaRESUMEN
A series of beta-aminoamides bearing triazolopiperazines have been discovered as potent, selective, and orally active dipeptidyl peptidase IV (DPP-4) inhibitors by extensive structure-activity relationship (SAR) studies around the triazolopiperazine moiety. Among these, compound 34b with excellent in vitro potency (IC50 = 4.3 nM) against DPP-4, high selectivity over other enzymes, and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in lean mice. On the basis of these properties, compound 34b has been profiled in detail. Further refinement of the triazolopiperazines resulted in the discovery of a series of extremely potent compounds with subnanomolar activity against DPP-4 (42b- 49b), that is, 4-fluorobenzyl-substituted compound 46b, which is notable for its superior potency (IC50 = 0.18 nM). X-ray crystal structure determination of compounds 34b and 46b in complex with DPP-4 enzyme revealed that (R)-stereochemistry at the 8-position of triazolopiperazines is strongly preferred over (S) with respect to DPP-4 inhibition.
Asunto(s)
Amidas/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV , Piperazinas/síntesis química , Pirazinas/síntesis química , Triazoles/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Animales , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/química , Perros , Prueba de Tolerancia a la Glucosa , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Piperazinas/farmacocinética , Piperazinas/farmacología , Pirazinas/farmacocinética , Pirazinas/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacocinética , Triazoles/farmacologíaRESUMEN
A series of benzodiazepines and benzazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of the benzazepinone series, compound 47, displayed potent, state-dependent block of hNa(v)1.7, and was orally efficacious in a rat model of neuropathic pain.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/química , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/clasificación , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Animales , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/farmacología , Estructura Molecular , Canal de Sodio Activado por Voltaje NAV1.7 , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/uso terapéutico , Relación Estructura-ActividadRESUMEN
Novel cyclopentane-based 3-phenyl-1-hydroxypropyl compounds were evaluated for inhibitory activity against the peripheral nerve sodium channel Na(V)1.7 and off-target activity against the cardiac potassium channel hERG. The stereochemistry of the hydroxyl group and substitution on the phenyl rings with either fluorinated O-alkyl or alkyl groups were found to be critical for conferring potency against Na(V)1.7. A benchmark compound from this series displayed efficacy in rat models of inflammatory and neuropathic pain.
Asunto(s)
Ciclopentanos/química , Ciclopentanos/farmacología , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Canales de Sodio/metabolismo , Animales , Ciclopentanos/síntesis química , Ciclopentanos/farmacocinética , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Bloqueadores de los Canales de Sodio/química , Bloqueadores de los Canales de Sodio/farmacocinética , Relación Estructura-ActividadRESUMEN
Optimization of the biological activity of a new class of non-peptidyl, pyridazinone derived human melanocortin subtype-4 receptor agonists is disclosed.
Asunto(s)
Diseño de Fármacos , Piridazinas/química , Piridazinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piridazinas/síntesis química , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.