Isoform selective PLD inhibition by novel, chiral 2,8-diazaspiro[4.5]decan-1-one derivatives

• Published in: Bioorganic & medicinal chemistry letters 2018-12, Vol.28 (23-24), p.3670-3673
• Main Authors: Waterson, Alex G., Scott, Sarah A., Kett, Nathan R., Blobaum, Anna L., Alex Brown, H., Lindsley, Craig W.
• Format: Article
• Language: English
• Subjects: Animals; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Half-Life; HEK293 Cells; Humans; Inhibitors; Inhibitory Concentration 50; Isoform; Phosphodiesterase; Phospholipase D; Phospholipase D - antagonists & inhibitors; Phospholipase D - metabolism; PLD; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - metabolism; Rats; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacokinetics; Stereoisomerism; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2018.10.033

[Display omitted] •A novel 2,8-diazaspiro[4.5]decan-1-one core affords enantioselective inhibition of PLD enzymes.•A single chemotype can produce PLD1, PLD2 and dual PLD1/PLD2 inhibitors.•The new series afford improvements in protein binding, predicted clearance and half-life in vivo.•Novelty allowed for the first, and only issued, US patent covering PLD inhibitors. 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  65 mL/min/kg) and very short half-lives in vivo (t1/2