ABSTRACT
The Rho kinase (ROCK) pathway is implicated in the pathogenesis of several conditions, including neurological diseases. In Huntington's disease (HD), ROCK is implicated in mutant huntingtin (HTT) aggregation and neurotoxicity, and members of the ROCK pathway are increased in HD mouse models and patients. To validate this mode of action as a potential treatment for HD, we sought a potent, selective, central nervous system (CNS)-penetrant ROCK inhibitor. Identifying a compound that could be dosed orally in mice with selectivity against other AGC kinases, including protein kinase G (PKG), whose inhibition could potentially activate the ROCK pathway, was paramount for the program. We describe the optimization of published ligands to identify a novel series of ROCK inhibitors based on a piperazine core. Morphing of the early series developed in-house by scaffold hopping enabled the identification of a compound exhibiting high potency and desired selectivity and demonstrating a robust pharmacodynamic (PD) effect by the inhibition of ROCK-mediated substrate (MYPT1) phosphorylation after oral dosing.
Subject(s)
Huntington Disease , Animals , Brain/metabolism , Disease Models, Animal , Huntingtin Protein/metabolism , Huntington Disease/drug therapy , Mice , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , rho-Associated KinasesABSTRACT
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
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
Subject(s)
Amides/chemistry , Azabicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Indoles/chemical synthesis , Piperazines/chemistry , Receptor, Cannabinoid, CB1/agonists , Animals , Azabicyclo Compounds/chemistry , Azabicyclo Compounds/pharmacology , Drug Design , Humans , Indoles/chemistry , Indoles/pharmacology , Mice , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptor, Cannabinoid, CB1/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.
ABSTRACT
Microwave-assisted organic synthesis (MAOS) is rapidly becoming recognized as a valuable tool for easing some of the bottlenecks in the drug discovery process. This article outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date.
