Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives.
Bioorg Med Chem Lett, 2018/12/15;28(23-24):3670-3673.
Waterson AG[1], Scott SA[2], Kett NR[3], Blobaum AL[4], Alex Brown H[5], Lindsley CW[6]
Affiliations
PMID: 30528979DOI: 10.1016/j.bmcl.2018.10.033
Impact factor: 2.94
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 < 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-diazaspiro[4.5]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: Inhibitors; Isoform; PLD; Phosphodiesterase; Phospholipase D
MeSH terms
Animals; Enzyme Inhibitors; HEK293 Cells; Half-Life; Humans; Inhibitory Concentration 50; Phospholipase D; Protein Isoforms; Rats; Spiro Compounds; Stereoisomerism; Structure-Activity Relationship
More resources
EndNote: Download