ABSTRACT
The synthesis and identification of sulfonamido-aryl ethers as potent bradykinin B1 receptor antagonists from a approximately 60,000 member encoded combinatorial library are reported. Two distinct series of compounds exhibiting different structure-activity relationships were identified in a bradykinin B1 whole-cell receptor-binding assay. Specific examples exhibit K(i) values of approximately 10nM.
Subject(s)
Bradykinin B1 Receptor Antagonists , Ethers/chemical synthesis , Sulfonamides/chemical synthesis , Animals , Cell Line , Combinatorial Chemistry Techniques , Humans , Small Molecule Libraries , Structure-Activity Relationship , Sulfonamides/pharmacologySubject(s)
Catalytic Domain , Nuclear Magnetic Resonance, Biomolecular/methods , Protein Tyrosine Phosphatases/chemistry , Amino Acid Motifs/genetics , Catalytic Domain/genetics , Gene Library , Hippocampus/chemistry , Hippocampus/enzymology , Hippocampus/metabolism , Humans , Protein Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 1 , Protein Tyrosine Phosphatases/genetics , src Homology Domains/geneticsABSTRACT
The first example of magic angle spinning NMR on crowns has been demonstrated. The ability to monitor a reaction on a crown and to confirm the structure of the reaction product directly on the crown without resorting to chemical cleavage should greatly enhance the utility of this convenient format for combinatorial chemistry.
ABSTRACT
Catalytic oxidations of primary, benzylic, and secondary alcohols to aldehydes and ketone using tetra-n-propylammonium perruthenate (TPAP) were carried out on resin supports for the first time. The reaction time course, percent conversion, and influence of catalyst amount have been determined by analyzing IR spectra taken directly on a single resin bead in real time. Using 0.2 equiv of TPAP, a 92-97% conversion of alcohol to aldehyde or ketone has been achieved in 0.7-4 h based on the rates (rate constants (1.9 x 10(-)(4))-(2.5 x 10(-)(3)) s(-)(1)) of disappearance and appearance of IR bands characteristic for alcohol, aldehyde, and ketone. The rapid adaptation of this oxidation method for solid-phase synthesis demonstrates that single-bead FTIR microspectroscopy is a powerful method for facilitating the time-consuming reaction optimization stage of combinatorial chemistry.
