Received for publication December 8, 2005.
Revised May 4, 2006.
Accepted for publication May 4, 2006.

The Pharmacology of Two Novel Long-acting Phosphodiesterase 3/4 Inhibitors RPL554 and RPL565

Abstract

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 (EFS)-induced contraction of guinea-pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 µM) and RPL565 (10 µM) (% control; 93 ± 1.2 and 84.4 ± 2.7, respectively). Contractile responses were suppressed for up to 12 hrs after termination of superfusion with RPL554 demonstrating a long duration of action. RPL554 and RPL565 inhibited in a concentration-dependent manner, lipopolysaccharide (LPS)-induced tumour necrosis factor (TNF) release from human monocytes (IC₅₀; 0.52µM (0.38 - 0.69) and 0.25 µM (0.18 - 0.35), respectively) and proliferation of human mononuclear cells to phytohaemagluttin (PHA) (IC₅₀; 0.46 µM (0.24 - 0.9) and 2.90 µM (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^-1) and RPL565 (10 mg kg^-1) administered orally significantly inhibited eosinophil recruitment following antigen challenge in ovalbumin-sensitised guinea-pigs. Similarly, inhalation of dry powder containing RPL554 by conscious guinea-pigs (25 % in micronised lactose) 1.5 h prior to 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 micronised 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.

Key words: Asthma, COPD, Guinea pig, Phosphodiesterase, Smooth muscle, inflammation