ABSTRACT
The subensemble kinetics of a platinum-sulfur covalent chemical reaction at the solution/surface interface of a model industrial catalyst support was examined using single-molecule fluorescence microscopy (SMFM) and was found to exhibit biexponential first-order kinetic behavior. The observed kinetics was a convolution of the observation probability and chemical reaction rate. These results suggest that deconvolution strategies may be broadly important for obtaining accurate chemical reaction kinetics with SMFM.
ABSTRACT
To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Quinolines/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Binding Sites , Blood Glucose/metabolism , Crystallography, X-Ray , Diabetes Mellitus, Experimental/metabolism , Dogs , Fluorescence Resonance Energy Transfer , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Ligands , Mice , Molecular Conformation , Protein Structure, Tertiary , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Weight Gain/drug effectsABSTRACT
Single-molecule fluorescence microscopy provided information about the real-time distribution of chemical reactivity on silicon oxide supports at the solution-surface interface, at a level of detail which would be unavailable from a traditional ensemble technique or from a technique that imaged the static physical properties of the surface. Chemical reactions on the surface were found to be uncorrelated; that is, the chemical reaction of one metal complex did not influence the location of a future chemical reaction of another metal complex.
ABSTRACT
Two series of conformationally constrained analogs of the FXR agonist GW 4064 1 were prepared. Replacement of the metabolically labile stilbene with either benzothiophene or naphthalene rings led to the identification of potent full agonists 2a and 2g.
Subject(s)
Isoxazoles/chemistry , Naphthalenes/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , Thiophenes/chemistry , Animals , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Isoxazoles/pharmacology , Naphthalenes/pharmacokinetics , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity Relationship , Thiophenes/pharmacokineticsABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a.
Subject(s)
Isoxazoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Crystallography, X-Ray , Fluorescence Resonance Energy Transfer , Isoxazoles/chemistry , Isoxazoles/pharmacology , Rats , Receptors, Cytoplasmic and Nuclear/metabolism , Structure-Activity RelationshipABSTRACT
Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model.