rpl-554 and Pneumonia

The pharmacology of two novel, trequinsin-like PDE3/4 inhibitors, RPL554 [9,10-dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido-[6,1-a]isoquinolin-4-one] and RPL565 [6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one], has been investigated in a number of in vitro and in vivo assays. Electrical field stimulation-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 microM) and RPL565 (10 microM) (percentage control; 93 +/- 1.2 and 84.4 +/- 2.7, respectively). Contractile responses were suppressed for up to 12 h after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 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 0.25 microM (0.18-0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC50; 0.46 microM (0.24-0.9) and 2.90 microM (1.6-5.4), respectively]. The inhibitory effect of these drugs in vitro was translated into anti-inflammatory activity in vivo. RPL554 (10 mg/kg) and RPL565 (10 mg/kg) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitized guinea pigs. Likewise, inhalation of dry powder containing RPL554 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 RPL554 (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. Thus, RPL554 and RPL565 are novel, long-acting PDE 3/4 inhibitors exhibiting a broad range of both bronchoprotective and anti-inflammatory activities.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Airway Resistance; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 3; Cyclic Nucleotide Phosphodiesterases, Type 4; Electric Stimulation; Guinea Pigs; Humans; In Vitro Techniques; Isoquinolines; Lung; Male; Monocytes; Muscle Contraction; Muscle, Smooth; Ovalbumin; Phosphodiesterase Inhibitors; Phytohemagglutinins; Platelet Aggregation Inhibitors; Pneumonia; Pyrimidinones; Tetrahydroisoquinolines; Trachea; Tumor Necrosis Factor-alpha