ABSTRACT
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.
Subject(s)
Benzamides/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Opioid, kappa/antagonists & inhibitors , Animals , Benzamides/chemistry , Benzamides/pharmacology , Brain/metabolism , CHO Cells , Chromatography, Liquid , Cricetinae , Cricetulus , HEK293 Cells , Humans , Pyrrolidines/chemistry , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Receptors, Opioid, kappa/metabolism , Stereoisomerism , Structure-Activity Relationship , Tandem Mass SpectrometryABSTRACT
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.
Subject(s)
Amides/chemistry , Drug Design , Indoles/chemical synthesis , PPAR delta/agonists , PPAR gamma/agonists , Animals , Combinatorial Chemistry Techniques , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Indoles/chemistry , Indoles/pharmacology , Molecular Structure , RatsABSTRACT
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.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Dipeptidyl Peptidase 4/blood , Drug Evaluation, Preclinical , Hydrogen Bonding , Male , Models, Molecular , Molecular Conformation , Protease Inhibitors/chemistry , Rats , Rats, Wistar , Spectrometry, FluorescenceABSTRACT
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.
