Ensifentrine (Ensifentrinum) is a PDE3/4 inhibitor, although its affinity for PDE3(IC50: 0.4 nM) is 3,440 times higher than that for PDE4(IC50: 1479 nM), that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis.

PDE4:1479 nM, PDE3:0.4 nM

Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by Ensifentrine (10 microM) (percentage control; 93 +/- 1.2). Contractile responses were suppressed for up to 12 h after termination of superfusion with Ensifentrine demonstrating a long duration of action. Ensifentrine4 inhibited, in a concentration-dependent manner, lipopolysaccharide-induced tumor necrosis factor alpha release from human monocytes [IC50; 0.52 microM (0.38-0.69)] and proliferation of human mononuclear cells to phytohemagglutinin [IC50; 0.46 microM (0.24-0.9)][2].

Ensifentrine administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing Ensifentrine by conscious guinea pigs (25% in micronized lactose) 1.5 h before antigen exposure significantly inhibited the recruitment of eosinophils to the airways. Exposure of conscious guinea pigs to inhalation of dry powder containing Ensifentrine (2.5%) and RPL565 (25%) in micronized lactose significantly inhibited histamine-induced plasma protein extravasation in the trachea and histamine-induced bronchoconstriction over a 5.5-h period[2].