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

• Published in: Bioorganic & medicinal chemistry letters Vol. 28; no. 23-24; pp. 3670 - 3673
• Main Authors: Waterson, Alex G., Scott, Sarah A., Kett, Nathan R., Blobaum, Anna L., Alex Brown, H., Lindsley, Craig W.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.12.2018
• Subjects: Inhibitors; Isoform; Phosphodiesterase; Phospholipase D; PLD; PLD; Isoform; Inhibitors; Phospholipase D; Phosphodiesterase
• 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 < 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.