RESUMEN
Arylphenylpyrrolidinylmethylphenoxybenzamides were found to have high affinity and selectivity for κ opioid receptors. On the basis of receptor binding assays in Chinese hamster ovary (CHO) cells expressing cloned human opioid receptors, (S)-3-fluoro-4-(4-((2-(3-fluorophenyl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (25) had a K(i) = 0.565 nM for κ opioid receptor binding while having a K(i) = 35.8 nM for µ opioid receptors and a K(i) = 211 nM for δ opioid receptor binding. Compound 25 was also a potent antagonist of κ opioid receptors when tested in vitro using a [(35)S]-guanosine 5'O-[3-thiotriphosphate] ([(35)S]GTP-γ-S) functional assay in CHO cells expressing cloned human opioid receptors. Compounds were also evaluated for potential use as receptor occupancy tracers. Tracer evaluation was done in vivo, using liquid chromatography-tandem mass spectrometry (LC/MS/MS) methods, precluding the need for radiolabeling. (S)-3-Chloro-4-(4-((2-(pyridine-3-yl)pyrrolidin-1-yl)methyl)phenoxy)benzamide (18) was found to have favorable properties for a tracer for receptor occupancy, including good specific versus nonspecific binding and good brain uptake.
Asunto(s)
Benzamidas/síntesis química , Pirrolidinas/síntesis química , Receptores Opioides kappa/antagonistas & inhibidores , Animales , Benzamidas/química , Benzamidas/farmacología , Encéfalo/metabolismo , Células CHO , Cromatografía Liquida , Cricetinae , Cricetulus , Células HEK293 , Humanos , Pirrolidinas/química , Pirrolidinas/farmacología , Ensayo de Unión Radioligante , Ratas , Receptores Opioides kappa/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Espectrometría de Masas en TándemRESUMEN
A series of potent amide linked PPARgamma/delta dual agonists (1a) has been discovered through rational design. In the ZDF rat model of type 2 diabetes, compound (R)-3-[4-(3-{1-[(5-chloro-1,3-dimethyl-1H-indole-2-carbonyl)-amino]-ethyl}-5-fluoro-phenoxy)-2-ethyl-phenyl]-propionic acid (42) from this series has demonstrated glucose lowering efficacy comparable to the marketed PPARgamma agonist rosiglitazone with less weight gain.
Asunto(s)
Amidas/química , Diseño de Fármacos , Indoles/síntesis química , PPAR delta/agonistas , PPAR gamma/agonistas , Animales , Técnicas Químicas Combinatorias , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Indoles/química , Indoles/farmacología , Estructura Molecular , RatasRESUMEN
A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Animales , Sitios de Unión , Simulación por Computador , Cristalografía por Rayos X , Dipeptidil Peptidasa 4/sangre , Evaluación Preclínica de Medicamentos , Enlace de Hidrógeno , Masculino , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/química , Ratas , Ratas Wistar , Espectrometría de FluorescenciaRESUMEN
The design and synthesis of the dual peroxisome proliferator-activated receptor (PPAR) gamma/delta agonist (R)-3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-butoxy]-2-ethyl-phenyl}-propionic acid (20) for the treatment of type 2 diabetes and associated dyslipidemia is described. The compound possesses a potent dual hPPAR gamma/delta agonist profile (IC(50) = 19 nM/4 nM; EC(50) = 102 nM/6 nM for hPPARgamma and hPPARdelta, respectively). In preclinical models, the compound improves insulin sensitivity and reverses diabetic hyperglycemia with less weight gain at a given level of glucose control relative to rosiglitazone.
Asunto(s)
Hipoglucemiantes/síntesis química , PPAR delta/agonistas , PPAR gamma/agonistas , Éteres Fenílicos/síntesis química , Fenilpropionatos/síntesis química , Aumento de Peso/efectos de los fármacos , Animales , Glucemia/metabolismo , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Dislipidemias/tratamiento farmacológico , Femenino , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Ratones , PPAR alfa/genética , Éteres Fenílicos/química , Éteres Fenílicos/farmacología , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ensayo de Unión Radioligante , Estereoisomerismo , Activación TranscripcionalRESUMEN
A series of benzylic piperazines (e.g., 4 and 5) attached to an 'address element', the dipeptide H-D-Tic-D-p-Cl-Phe-OH, 3 has been identified as ligands for the melanocortin subtype-4 receptor (MC4R). We describe herein the structure-activity relationship (SAR) studies on the N-terminal residue of the 'address element'. Several novel dipeptides and reduced dipeptides with high MC4R binding affinities and selectivity emerged from this SAR study.