RESUMEN
The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.
Asunto(s)
Antivirales/farmacología , Péptidos Cíclicos/farmacología , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Antivirales/farmacocinética , Células CHO , Cricetulus , Descubrimiento de Drogas , Estabilidad de Medicamentos , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Microsomas Hepáticos/metabolismo , Estructura Molecular , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/metabolismo , Péptidos Cíclicos/farmacocinética , Ratas , Inhibidores de Serina Proteinasa/síntesis química , Inhibidores de Serina Proteinasa/metabolismo , Inhibidores de Serina Proteinasa/farmacocinética , Relación Estructura-ActividadRESUMEN
A series of tripeptidic acylsulfonamide inhibitors of HCV NS3 protease were prepared that explored structure-activity relationships (SARs) at the P4 position, and their in vitro and in vivo properties were evaluated. Enhanced potency was observed in a series of P4 ureas; however, the PK profiles of these analogues were less than optimal. In an effort to overcome the PK shortcomings, modifications to the P3-P4 junction were made. This included a strategy in which one of the two urea N-H groups was either N-methylated or replaced with an oxygen atom. The former approach provided a series of regioisomeric N-methylated ureas while the latter gave rise to P4 reverse carbamates, both of which retained potent NS3 inhibitory properties while relying upon an alternative H-bond donor topology. Details of the SARs and PK profiles of these analogues are provided.
Asunto(s)
Antivirales/química , Carbamatos/química , Inhibidores de Proteasas/química , Urea/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Sitios de Unión , Semivida , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Humanos , Enlace de Hidrógeno , Hígado/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , Ratas , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH3 and CF3 analogues, respectively, providing insight into the deployment of this unique amino acid.
RESUMEN
A series of potent and novel acylsulfonamide-bearing triazines were synthesized and the structure-activity relationships (SARs) as HCV entry inhibitors were evaluated. This acylsulfonamide series was derived from an early lead, 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid wherein the carboxylic acid was replaced with an acylsulfonamide moiety. This structural modification provided a class of compounds which projected an additional vector off the terminus of the acylsulfonamide functionality as a means to drive activity. This effort led to the discovery of potent analogues within this series that demonstrated sub-nanomolar EC50 values in the HCV pseudotype particle (HCVpp) assay.
Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Fusión de Membrana/efectos de los fármacos , Triazinas/farmacología , Animales , Antivirales/química , Antivirales/farmacocinética , Hepacivirus/fisiología , Humanos , Ratas , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacocinéticaRESUMEN
The design and synthesis of a series of tripeptide acylsulfonamides as potent inhibitors of the HCV NS3/4A serine protease is described. These analogues house a C4 aryl, C4 hydroxy-proline at the S2 position of the tripeptide scaffold. Information relating to structure-activity relationships as well as the pharmacokinetic and cardiovascular profiles of these analogues is provided.
Asunto(s)
Antivirales/química , Hepacivirus/enzimología , Oligopéptidos/química , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/farmacocinética , Antivirales/farmacología , Semivida , Corazón/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Humanos , Técnicas In Vitro , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Prolina/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Relación Estructura-Actividad , Sulfonamidas/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).
Asunto(s)
Antivirales/química , Hepacivirus/efectos de los fármacos , Isoquinolinas/uso terapéutico , Oligopéptidos/química , Sulfonamidas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/administración & dosificación , Antivirales/farmacocinética , Antivirales/farmacología , Perros , Esquema de Medicación , Farmacorresistencia Viral , Hepacivirus/genética , Macaca fascicularis , Masculino , Modelos Moleculares , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Conejos , Ratas Sprague-Dawley , Replicón , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
BACKGROUND: FGF21,as a member of the fibroblast growth factor superfamily, is an important endogenous regulator to systemic glucose and lipid metabolism. Elevated serum FGF21 levels have been reported in subjects with coronary heart disease and carotid artery plaques. The formation and apoptosis of foam cell, induced by ox-LDL and oxysterols, are key steps in the development of atherosclerosis. METHODS: In this study, THP1 derived macrophages were induced into foam cells by ox-LDL or sterols. The formation and apoptosis of foam cells treated with or without FGF21 were analyzed. RESULTS: We demonstrated that the accumulation of cholesterol was decreased after FGF21 treatment in THP1 macrophage derived foam cells. Consistently, the apoptosis of macrophage was alleviated dramatically with FGF21 treatment. ERK1/2 knockdown didn't abrogate the effect of FGF21 on THP1 macrophage derived foam cells. However, FGF21 suppressed the induced expression of CHOP and DR5 in THP1 macrophage derived foam cells. CONCLUSION: FGF21 protects against the formation and apoptosis of THP1 macrophages derived foam cells through suppressing the expression of CHOP.
Asunto(s)
Apoptosis/fisiología , Factores de Crecimiento de Fibroblastos/farmacología , Células Espumosas/metabolismo , Lipoproteínas LDL/toxicidad , Factor de Transcripción CHOP/antagonistas & inhibidores , Factor de Transcripción CHOP/biosíntesis , Apoptosis/efectos de los fármacos , Células Espumosas/efectos de los fármacos , Regulación de la Expresión Génica , Humanos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismoRESUMEN
PURPOSE: Epidural/spinal opioids are increasingly used to relieve parturients' pain in labour. Some studies indicate that opioids can induce side effects in neonates, such as respiratory depression and neurobehavioural changes. This meta-analysis aimed to clarify the effects of opioids in labour analgesia on neonates. SOURCE: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE™ were searched for relevant randomized controlled trials (RCTs). The neonatal data of Apgar scores, Neurological and Adaptive Capacity Scores (NACS), and umbilical cord pH values were extracted. Statistical analyses were carried out using Review Manager 5.2 and Stata(®) 10. PRINCIPAL FINDINGS: Twenty-one trials with 2,859 participants were included in our meta-analysis. No difference in the incidence of Apgar scores < 7 was shown between the opioid and control groups at one minute (risk difference [RD] 0.0%, 95% confidence interval [CI]: -3.0 to 2.0, P = 0.78; I (2) = 0%, 95% CI: 0 to 50) and at five minutes (RD -1.0%, 95% CI: -2.0 to 1.0, P = 0.31; I(2) = 0%, 95% CI: 0 to 50). No significant differences were found in the NACS at two hours (mean difference [MD] -0.35, 95% CI: -1.70 to 1.01, P = 0.62; I(2) = 0%, 95% CI: 0 to 79) and at 24 hr (MD -0.45, 95% CI: -1.36 to 0.46, P = 0.33; I(2) = 3%, 95% CI: 0 to 26). Also, no significant differences were found in umbilical cord artery pH (MD -0.02, 95% CI: -0.06 to 0.03, P = 0.48; I(2) = 80%, 95% CI: 46 to 92) and vein pH (MD -0.03, 95% CI: -0.07 to 0.00, P = 0.08; I(2) = 77%, 95% CI: 36 to 91). No significant publication bias was found. CONCLUSION: The common doses of fentanyl and sufentanil used with an epidural/spinal technique in labour analgesia are safe for neonates up to 24 hr after delivery. In future studies, more attention should be paid to the long-term side effects in neonates.
Asunto(s)
Analgesia Epidural/efectos adversos , Analgesia Obstétrica/efectos adversos , Analgésicos Opioides/efectos adversos , Femenino , Fentanilo/efectos adversos , Humanos , Recién Nacido , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Sufentanilo/efectos adversosRESUMEN
The discovery of BMS-605339 (35), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropylacylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1' site of the protease. The identification of 35 was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound 35 which demonstrated antiviral activity in HCV-infected patients.
Asunto(s)
Antivirales/uso terapéutico , Descubrimiento de Drogas , Hepatitis C/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Perros , Evaluación Preclínica de Medicamentos , Humanos , Isoquinolinas/química , Modelos Moleculares , Inhibidores de Proteasas/química , Sulfonamidas/químicaRESUMEN
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).
Asunto(s)
Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Isoquinolinas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/sangre , Antivirales/química , Perros , Humanos , Isoquinolinas/sangre , Isoquinolinas/química , Modelos Moleculares , Inhibidores de Proteasas/sangre , Inhibidores de Proteasas/química , Conejos , Ratas , Sulfonamidas/sangre , Sulfonamidas/químicaRESUMEN
Acrylamide (S)-6, a potent and efficacious KCNQ2 (Kv7.2) opener, demonstrated significant activity in two models of neuropathic pain and in the formalin test, suggesting that KCNQ2 openers may be useful in the treatment of neuropathic pain including diabetic neuropathy.
Asunto(s)
Acrilamidas/química , Acrilamidas/farmacología , Canal de Potasio KCNQ2/metabolismo , Neuralgia/tratamiento farmacológico , Acrilamidas/síntesis química , Animales , Canal de Potasio KCNQ2/química , Masculino , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-DawleyRESUMEN
Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined with alfa interferon and/or the NS5A replication complex inhibitor daclatasvir. ASV competitively binds to the NS3/4A protease complex, with K(i) values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) and 1b (J4L6S), respectively. Selectivity was demonstrated by the absence of any significant activity against the closely related GB virus-B NS3 protease and a panel of human serine or cysteine proteases. In cell culture, ASV inhibited replication of HCV replicons representing genotypes 1 and 4, with 50% effective concentrations (EC(50)s) ranging from 1 to 4 nM, and had weaker activity against genotypes 2 and 3 (EC(50), 67 to 1,162 nM). Selectivity was again demonstrated by the absence of activity (EC(50), >12 µM) against a panel of other RNA viruses. ASV exhibited additive or synergistic activity in combination studies with alfa interferon, ribavirin, and/or inhibitors specifically targeting NS5A or NS5B. Plasma and tissue exposures in vivo in several animal species indicated that ASV displayed a hepatotropic disposition (liver-to-plasma ratios ranging from 40- to 359-fold across species). Twenty-four hours postdose, liver exposures across all species tested were ≥110-fold above the inhibitor EC(50)s observed with HCV genotype-1 replicons. Based on these virologic and exposure properties, ASV holds promise for future utility in a combination with other anti-HCV agents in the treatment of HCV-infected patients.
Asunto(s)
Hepacivirus/efectos de los fármacos , Hepacivirus/patogenicidad , Isoquinolinas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Línea Celular , Perros , Genotipo , Haplorrinos , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Isoquinolinas/farmacología , Masculino , Ratones , Ratas , Sulfonamidas/farmacologíaRESUMEN
(R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives (e.g., 3 and 4) were synthesized as novel melatoninergic ligands with significantly lower vasoconstrictive activity in vitro in the rat tail artery. Binding affinity assays were performed on cloned human MT1 and MT2 receptors stably expressed in NIH3T3 cells.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Melatonina/agonistas , Vasoconstrictores/química , Vasoconstrictores/farmacología , Animales , Benzofuranos/síntesis química , Clonación Molecular , Humanos , Ligandos , Melatonina/farmacología , Ratones , Estructura Molecular , Células 3T3 NIH , Unión Proteica/efectos de los fármacos , Ratas , Receptor de Melatonina MT1/efectos de los fármacos , Receptor de Melatonina MT1/metabolismo , Receptor de Melatonina MT2/efectos de los fármacos , Receptor de Melatonina MT2/metabolismo , Proteínas Recombinantes/efectos de los fármacos , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/síntesis químicaRESUMEN
Replacement of the morpholinyl moiety in (S,E)-N-[1-(3-morpholinophenyl)ethyl]-3-phenylacrylamide (1) with heteroaryl groups led to the identification of (S,E)-N-1-[3-(6-fluoropyridin-3-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (5) as a potent KCNQ2 potassium channel opener. Among this series of heteroaryl substituted acrylamides, (S,E)-N-1-[3-(1H-pyrazol-1-yl)phenyl]ethyl-3-(2-fluorophenyl)acrylamide (9) exhibits balanced potency and efficacy. The syntheses and the KCNQ2 opener activity of this series of acrylamides are described.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Canales de Potasio con Entrada de Voltaje/metabolismo , Acrilamidas/síntesis química , Acrilamidas/farmacología , Animales , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Canal de Potasio KCNQ2 , Estructura MolecularRESUMEN
N-[2-[2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide 3a was synthesized as an orally bioavailable agonist at MT1 and MT2 melatonin receptors with significantly low vasoconstrictive activity.
Asunto(s)
Acetamidas/farmacocinética , Benzofuranos/farmacocinética , Receptor de Melatonina MT1/agonistas , Receptor de Melatonina MT2/agonistas , Acetamidas/síntesis química , Acetamidas/toxicidad , Administración Oral , Animales , Benzofuranos/síntesis química , Benzofuranos/toxicidad , Disponibilidad Biológica , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/biosíntesis , Relación Dosis-Respuesta a Droga , Humanos , Técnicas In Vitro , Ratones , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Células 3T3 NIH , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
Bioisosteric replacement studies led to the identification of N-(1-benzo[1,3]dioxol-5-yl-ethyl)-3-(2-chloro-phenyl)-acrylamide ((S)-3) as a highly potent KCNQ2 opener, and 3-(2,6-difluoro-phenyl)-N-[1-(2,3-dihydro-benzofuran-5-yl)-ethyl]-acrylamide ((S)-4), and N-[1-(2,3-dihydro-1H-indol-5-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-5) as highly efficacious KCNQ2 openers. In contrast, their respective R enantiomers showed significantly less or no appreciable KCNQ2 opener activity even at the highest concentration tested (10 microM). Because of its high potency and moderate efficacy as well as its convenient synthesis, (+/-)-3 was selected as a reference compound for analyzing efficacies of KCNQ openers in electrophysiology studies. Compounds (S)-4 and (S)-5 demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices. The synthesis and the KCNQ2 opener activity of these acrylamides are described.
Asunto(s)
Acrilamidas/química , Benzofuranos/química , Canales de Potasio con Entrada de Voltaje/metabolismo , Acrilamidas/farmacología , Animales , Benzofuranos/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Canal de Potasio KCNQ2 , RatasRESUMEN
A series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. From this series of benzoxazole derivatives, compounds 14 and 17 were identified as melatonin receptor agonists.
Asunto(s)
Benzoxazoles/síntesis química , Receptores de Melatonina/agonistas , Benzoxazoles/farmacología , Sitios de Unión , Línea Celular , Diseño de Fármacos , Humanos , Ligandos , Melatonina/análogos & derivados , Melatonina/metabolismo , Ensayo de Unión Radioligante , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Melatonina/metabolismo , Relación Estructura-ActividadRESUMEN
A new class of acrylamides was synthesized, and the effects of these analogues on outward potassium current were evaluated by using two electrode voltage clamp recordings from Xenopus laevis oocytes expressing cloned mKCNQ2 channels. SAR studies indicated that the pharmacophore of the acrylamide series includes the (S) absolute configuration at the (1-phenyl)ethyl moiety and the alpha,beta-unsaturated acrylamide functionality with a free NH. This study identified (S)-N-[1-(3-morpholin-4-yl-phenyl)-ethyl]-3-phenyl-acrylamide ((S)-1) and (S)-N-[1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethyl]-3-(4-fluoro-phenyl)-acrylamide ((S)-2) as KCNQ2 openers for further electrophysiological evaluations. These two acrylamides demonstrated significant activity in the cortical spreading depression model of migraine as we reported previously.
Asunto(s)
Acrilamidas/síntesis química , Cinamatos/síntesis química , Morfolinas/síntesis química , Canales de Potasio/efectos de los fármacos , Acrilamidas/química , Acrilamidas/farmacología , Animales , Cinamatos/química , Cinamatos/farmacología , Depresión de Propagación Cortical/efectos de los fármacos , Humanos , Canal de Potasio KCNQ2 , Ratones , Morfolinas/química , Morfolinas/farmacología , Oocitos/efectos de los fármacos , Oocitos/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/fisiología , Canales de Potasio con Entrada de Voltaje , Estereoisomerismo , Relación Estructura-Actividad , Xenopus laevisRESUMEN
(S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide ((S)-2) was identified as a potent and efficacious KCNQ2 opener. This compound demonstrated significant activity in reducing neuronal hyperexcitability in rat hippocampal slices, and the inhibition mediated by (S)-2 was reversed by the KCNQ blocker linopirdine.
Asunto(s)
Acrilamidas/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Oxazinas/farmacología , Canales de Potasio/efectos de los fármacos , Acrilamidas/síntesis química , Animales , Relación Dosis-Respuesta a Droga , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Canal de Potasio KCNQ2 , Riñón/citología , Riñón/efectos de los fármacos , Riñón/metabolismo , Ratones , Estructura Molecular , Neuronas/metabolismo , Neuronas/patología , Oxazinas/síntesis química , Técnicas de Placa-Clamp , Canales de Potasio/genética , Canales de Potasio/metabolismo , Canales de Potasio con Entrada de Voltaje , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of benzoxazole derivatives was synthesized and evaluated as melatoninergic ligands. The binding affinity of these compounds for human MT(1) and MT(2) receptors was determined using 2-[(125)I]-iodomelatonin as the radioligand. The results of the SAR studies in this series led to the identification of compound 28, which exhibited better MT(1) and MT(2) receptor affinities than melatonin itself. This work also established the benzoxazole nucleus as a melatoninergic pharmacophore, which served as an isosteric replacement to the previously established alkoxyaryl core.