RESUMO
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.
Assuntos
Benzamidas/síntese química , Pirrolidinas/síntese química , Receptores Opioides kappa/antagonistas & inibidores , Animais , Benzamidas/química , Benzamidas/farmacologia , Encéfalo/metabolismo , Células CHO , Cromatografia Líquida , Cricetinae , Cricetulus , Células HEK293 , Humanos , Pirrolidinas/química , Pirrolidinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Opioides kappa/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Espectrometria de Massas em TandemRESUMO
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.
Assuntos
Amidas/química , Desenho de Fármacos , Indóis/síntese química , PPAR delta/agonistas , PPAR gama/agonistas , Animais , Técnicas de Química Combinatória , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Indóis/química , Indóis/farmacologia , Estrutura Molecular , RatosRESUMO
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.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Dipeptidil Peptidase 4/sangue , Avaliação Pré-Clínica de Medicamentos , Ligação de Hidrogênio , Masculino , Modelos Moleculares , Conformação Molecular , Inibidores de Proteases/química , Ratos , Ratos Wistar , Espectrometria de FluorescênciaRESUMO
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.
