Isoform selective PLD inhibition by novel,chiral 2,8-diazaspiro[4.5]decan-1-one derivatives |
| |
| Authors: | Alex G. Waterson Sarah A. Scott Nathan R. Kett Anna L. Blobaum H. Alex Brown Craig W. Lindsley |
| |
| Affiliation: | 1. Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA;2. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;3. Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA;4. Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA;5. Vanderbilt Institute of Chemical Biology, Vanderbilt University/Vanderbilt University Medical Center, Nashville, TN 37232, USA |
| |
| Abstract: | This letter describes the on-going SAR efforts to develop PLD1, PLD2 and dual PLD1/2 inhibitors with improved physiochemical and disposition properties as well as securing intellectual property position. Previous PLD inhibitors, based on a triazaspiro[4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fu?hep?>?65?mL/min/kg) and very short half-lives in vivo (t1/2?3 character. This new core demonstrated enantioselective inhibition of the individual PLD isoforms, enhanced free fraction (rat, human fu?hep?～?43?mL/min/kg), improved half-lives in vivo (t1/2?>?3?h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors. |
| |
| Keywords: | PLD Phospholipase D Isoform Inhibitors Phosphodiesterase |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
