ABSTRACT
d-Serine is a coagonist of the N-methyl d-aspartate (NMDA) receptor, a key excitatory neurotransmitter receptor. In the brain, d-serine is synthesized from its l-isomer by serine racemase and is metabolized by the D-amino acid oxidase (DAO, DAAO). Many studies have linked decreased d-serine concentration and/or increased DAO expression and enzyme activity to NMDA dysfunction and schizophrenia. Thus, it is feasible to employ DAO inhibitors for the treatment of schizophrenia and other indications. Powered by the Schrödinger computational modeling platform, we initiated a research program to identify novel DAO inhibitors with the best-in-class properties. The program execution leveraged an hDAO FEP+ model to prospectively predict compound potency. A new class of DAO inhibitors with desirable properties has been discovered from this endeavor. Our modeling technology on this program has not only enhanced the efficiency of structure-activity relationship development but also helped to identify a previously unexplored subpocket for further optimization.
Subject(s)
N-Methylaspartate , Schizophrenia , D-Amino-Acid Oxidase/metabolism , Humans , Receptors, N-Methyl-D-Aspartate/metabolism , Serine/metabolism , Structure-Activity RelationshipABSTRACT
The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.
Subject(s)
Azides/chemistry , Carbamates/chemical synthesis , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Urea/chemical synthesis , Carbamates/chemistry , Carboxylic Acids/chemistry , Equipment Design , Mass Spectrometry/instrumentation , Mass Spectrometry/methods , Molecular Structure , Sensitivity and Specificity , Stereoisomerism , Urea/analogs & derivatives , Urea/chemistryABSTRACT
[reaction: see text] A three-step synthesis of cyclohexane-1,3-dione (CHD) resin 6 on polystyrene resin is described. Resin 6 was used to prepare an amide library of high purity by microwave-assisted serial "capture and release" and can be recycled for this purpose. High-loading CHD resin 10 was also shown to scavenge allyl cations in solution.