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

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 f_u < 0.03), high predicted hepatic clearance (rat CL_hep > 65 mL/min/kg) and very short half-lives in vivo (t_1/2 < 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 f_u < 0.13), engendered moderate predicted hepatic clearance (rat CL_hep ∼ 43 mL/min/kg), improved half-lives in vivo (t_1/2 > 3 h), and led to the first issued US patent claiming composition of matter for small molecule PLD inhibitors.