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 |
| |
Institution: | 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 triazaspiro4.5]decanone core proved to be highly selective PLD2 inhibitors, but with low plasma free fraction (rat, human fu?<?0.03), high predicted hepatic clearance (rat CLhep?>?65?mL/min/kg) and very short half-lives in vivo (t1/2?<?0.15?h). Removal of a nitrogen atom from this core generated a 2,8-diazaspiro4.5]decanone core, harboring a new chiral center, as well as increased sp3 character. This new core demonstrated enantioselective inhibition of the individual PLD isoforms, enhanced free fraction (rat, human fu?<?0.13), engendered moderate predicted hepatic clearance (rat CLhep?~?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! |
|