RESUMEN
The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.
Asunto(s)
Bencimidazoles/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Bencimidazoles/farmacología , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Canal de Potasio ERG1 , Electrofisiología/métodos , Canales de Potasio Éter-A-Go-Go/química , Humanos , Hipnóticos y Sedantes/farmacología , Concentración 50 Inhibidora , Cinética , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Morfolinas/química , Nitrógeno/química , Piperidinas/química , Receptores Histamínicos H1/química , Relación Estructura-ActividadRESUMEN
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Asunto(s)
Ciclopropanos/farmacología , Neuralgia/tratamiento farmacológico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Milnaciprán , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neuralgia/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Nervios Espinales/patología , Nervios Espinales/cirugía , Relación Estructura-ActividadRESUMEN
A series of piperazinebenzylalcohols were prepared and studied to compare with their ketone and amine analogs as MC4R antagonists. Several benzylalcohols such as 14a and 14g displayed low nanomolar binding affinities (K(i)<10 nM), and high selectivities over other melanocortin receptor subtypes.
Asunto(s)
Aminas/metabolismo , Alcoholes Bencílicos/metabolismo , Cetonas/metabolismo , Piperazinas/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , Aminas/síntesis química , Aminas/química , Sustitución de Aminoácidos , Animales , Alcoholes Bencílicos/síntesis química , Alcoholes Bencílicos/química , Unión Competitiva , Línea Celular , Humanos , Cetonas/síntesis química , Cetonas/química , Ligandos , Melanocortinas/antagonistas & inhibidores , Melanocortinas/metabolismo , Piperazinas/síntesis química , Piperazinas/química , Unión Proteica , Ratas , Receptor de Melanocortina Tipo 4/química , Relación Estructura-ActividadRESUMEN
Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas de Transporte de Neurotransmisores/química , Animales , Células CACO-2 , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/farmacología , Modelos Químicos , Neurotransmisores/metabolismo , Proteínas de Transporte de Neurotransmisores/antagonistas & inhibidores , Norepinefrina/química , Dolor , Ratas , Relación Estructura-ActividadRESUMEN
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Norepinefrina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antidepresivos/química , Técnicas Químicas Combinatorias , Ciclopropanos/química , Humanos , Concentración 50 Inhibidora , Milnaciprán , Estructura Molecular , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8-12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia.
Asunto(s)
Bencilaminas/farmacología , Caquexia/tratamiento farmacológico , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Animales , Bencilaminas/síntesis química , Bencilaminas/química , Células CACO-2 , Carcinoma Pulmonar de Lewis , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Conformación Molecular , Piperazinas/síntesis química , Piperazinas/química , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Factores de Tiempo , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Based on 3-phenylpropionamides, a series of 3-arylpyrrolidine-2-carboxamide derivatives was designed and synthesized to study the effect of cyclizations as melanocortin-4 receptor ligands. It was found that the 2R,3R-pyrrolidine isomer possessed the most potent affinity among the four stereoisomers.
Asunto(s)
Diseño de Fármacos , Pirrolidinas/síntesis química , Receptor de Melanocortina Tipo 4/agonistas , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Ciclización , Estructura Molecular , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacología , Ratas , Receptor de Melanocortina Tipo 4/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of piperazinephenethylamines were synthesized to study the contribution of a basic amine to binding affinity at the melanocortin-4 receptor. Several potent compounds from this series possessed subnanomolar K(i) values in a competition binding assay.
Asunto(s)
Fenetilaminas/química , Fenetilaminas/farmacología , Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , Animales , Bencilaminas/metabolismo , Concentración 50 Inhibidora , Cinética , Fenetilaminas/metabolismo , Piperazinas/metabolismo , Relación Estructura-ActividadRESUMEN
Piperazinebenzylamine derivatives from trans-4-(4-chlorophenyl)tetrahydrothiophene-3-carboxylic acid 6 and its S-oxide 7 and sulfone 8, and the tetrahydrofuran 9 and its two regioisomers 11 and 13 were synthesized and studied for their binding affinities at the human melanocortin-4 receptor. These five-membered ring constrained compounds possessed similar or lower potency compared to the acyclic analogs.
Asunto(s)
Furanos/síntesis química , Furanos/farmacología , Piperazinas/síntesis química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/efectos de los fármacos , Tiofenos/síntesis química , Tiofenos/farmacología , Técnicas Químicas Combinatorias , Furanos/química , Humanos , Ligandos , Estructura Molecular , Piperazinas/química , Tiofenos/químicaRESUMEN
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.
Asunto(s)
Pirrolidinas/química , Pirrolidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.
Asunto(s)
Amidas/síntesis química , Bencilaminas/síntesis química , Piperazinas/síntesis química , Piridinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/farmacología , Animales , Bencilaminas/farmacocinética , Bencilaminas/farmacología , Caquexia/tratamiento farmacológico , Caquexia/etiología , Carcinoma Pulmonar de Lewis/complicaciones , Línea Celular , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Diseño de Fármacos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Trasplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of trans-N-alkyl-4-(4-chlorophenyl)pyrrolidine-3-carboxamides of piperazinecyclohexanemethylamines was synthesized and characterized for binding and function at the melanocortin-4 receptor (MC4R), and several potent benzylamine derivatives were identified. Compound 18 v was found to bind MC4R with potent affinity (K(i)=0.5 nM) and high selectivity over the other melanocortin subtypes and behaved as a functional antagonist (IC(50)=48 nM).
Asunto(s)
Amidas/química , Ácidos Carboxílicos/química , Compuestos de Cloro/síntesis química , Ciclohexanos/química , Piperazinas/química , Pirrolidinas/química , Receptor de Melanocortina Tipo 4/metabolismo , Compuestos de Cloro/química , Ciclohexanos/farmacología , Ligandos , Estructura Molecular , Piperazina , Receptor de Melanocortina Tipo 4/agonistas , Relación Estructura-ActividadRESUMEN
A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.
Asunto(s)
Caquexia/tratamiento farmacológico , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Caquexia/etiología , AMP Cíclico/metabolismo , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Trasplante de Neoplasias , Neoplasias Experimentales/complicaciones , Piperazinas/farmacocinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , beta-Alanina/síntesis química , beta-Alanina/farmacocinética , beta-Alanina/farmacologíaRESUMEN
A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 20f-1 and 20f-2 displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-compound 20f-1 possessed a K(i) of 11nM and an EC(50) of 24nM, while its 3R,4S-isomer 20f-2 exhibited a K(i) of 8.6 and an IC(50) of 65nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 20f-1 also demonstrated efficacy in diet-induced obese rats.
Asunto(s)
Pirrolidinas/síntesis química , Receptor de Melanocortina Tipo 4/agonistas , Animales , Disponibilidad Biológica , Humanos , Inyecciones Intravenosas , Unión Proteica/fisiología , Pirrolidinas/administración & dosificación , Pirrolidinas/metabolismo , Ratas , Ratas Zucker , Receptor de Melanocortina Tipo 4/metabolismoRESUMEN
A series of pyrrolidinones derived from phenylalaninepiperazines were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor. In addition to their high binding affinities, these compounds displayed high functional potencies. 12a had a K(i) of 0.94 nM in binding and IC(50) of 21 nM in functional activity. 12a also demonstrated efficacy in a mouse cachexia model.
Asunto(s)
Pirrolidinonas/química , Pirrolidinonas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , Alquilación , Aminas/química , Animales , Encéfalo/efectos de los fármacos , Humanos , Ligandos , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Pirrolidinonas/síntesis química , Pirrolidinonas/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of pyrrolidine derivatives were synthesized and characterized as potent agonists of the human melanocortin-4 receptor. For example, 28c had a K(i) of 13 nM in binding affinity and EC(50) of 6.9 nM in agonist potency with an intrinsic activity of 100% of the endogenous ligand alpha-MSH.
Asunto(s)
Pirrolidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Línea Celular , HumanosRESUMEN
A series of pyrrolidinones derived from phenylalanines were synthesized as potent antagonists of the human melanocortin-4 receptor. These compounds showed high potencies and selectivities, and several of them had good oral bioavailabilities. In addition, 12e demonstrated in vivo efficacy in a murine cachexia model.
Asunto(s)
Caquexia/tratamiento farmacológico , Pirrolidinonas/química , Pirrolidinonas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Composición Corporal , Peso Corporal , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura Molecular , Pirrolidinonas/administración & dosificación , Pirrolidinonas/uso terapéutico , Relación Estructura-ActividadRESUMEN
A series of alpha-benzylpropionylpiperazines were synthesized and tested as antagonists of the melanocortin-4 receptor. In addition to its high potency and selectivity, R-11a had desirable pharmacokinetic properties including high brain penetration in mice.
Asunto(s)
Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Receptor de Melanocortina Tipo 4/metabolismo , Amidas/química , Animales , Humanos , Ligandos , Ratones , Estructura Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of 3-arylpropionylpiperazines were synthesized as antagonists of the melanocortin-4 receptor. Their potency was found to be increased by replacing the alpha-methyl substituent of the initial lead 11 with a larger s-Bu or i-Bu group. Further potency enhancement was observed when a glycine or beta-alanine was incorporated onto the benzylamine. Some compounds demonstrated good potency, moderate selectivity, and oral bioavailability.
Asunto(s)
Piperazinas/química , Piperazinas/farmacología , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Animales , Bencilaminas/química , Humanos , Ratones , Estructura Molecular , Piperazina , Piperazinas/síntesis química , Piperazinas/farmacocinética , Receptor de Melanocortina Tipo 4/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 2-pyridinylpiperazines derived from beta-Ala-(2,4-Cl)Phe dipeptide was synthesized for the study of their SARs and possible interactions with the MC4 receptor. Compounds such as 11k (Ki=6.5 nM) possessed high potency.