The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 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]

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-induced contraction of guinea pig superfused isolated tracheal preparations was significantly inhibited by RPL554 (10 M) and RPL565 (10 M) (percentage control; 93 Ϯ 1.2 and 84.4 Ϯ 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 ␣ release from human monocytes [IC 50 ; 0.52 M (0.38 -0.69) and 0.25 M (0.18 -0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [IC 50 ; 0.46 M (0.24 -0.9) and 2.90 M (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.It is now recognized that the second messenger cAMP plays a pivotal role in the regulation of cell function, and cyclic nucleotide phosphodiesterases (PDEs) are a diverse family of enzymes (1-11) responsible for the degradation of cAMP and are therefore potential drug targets for modulating cell function (Essayan, 2001). In the context of lung diseases, it is of particular interest that inhibiting the PDE3 and PDE4 isoenzymes can modulate the function of a variety This work was supported by Vernalis Plc. Article, publication date, and citation information can be found at

Dual PDE3/4 and PDE4 Inhibitors: Novel Treatments For COPD and Other Inflammatory Airway Diseases

“…More recently, another dual PDE3 and PDE4 inhibitor RPL554 has been described that is derived from a series of analogues of trequinsin which exhibits both bronchodilator and anti‐inflammatory activities in pre‐clinical in vitro and in vivo model systems . RPL554 also produces a rapid, significant and sustained bronchodilator effect in patients with mild–moderate COPD and also in patients with asthma, when administered by the inhaled route and is also bronchoprotective against methacholine challenge.…”

Phosphodiesterase Inhibitors for the Treatment of Asthma and Chronic Obstructive Pulmonary Disease

“…More recently, another dual PDE3 and PDE4 inhibitor RPL 554 has been described that is derived from a series of analogues of trequinsin, which exhibits both bronchodilatory and anti-inflammatory activities in preclinical in vitro and in vivo model systems [110]. RPL 554 also produces a rapid, significant and sustained bronchodilatory effect in patients with mild-to-moderate COPD and in asthma patients, when administered by the inhaled route, and is also bronchoprotective against methacholine challenge [111].…”

Cigarette smoke up‐regulates PDE3 and PDE4 to decrease cAMP in airway cells

“…Even though RPL554 is considered as one of the most selective PDE3 inhibitors based on an about 3000× higher IC 50 value for purified human platelet PDE3 compared to neutrophil PDE4 (PDE3: 0.4 nM; PDE4:1479 nM) (Boswell‐Smith et al ., 2006), a growing body of evidence suggest that dual inhibition of PDE3 and PDE4, using higher levels of inhibitor (10 μM or 0.018 mg·kg −1 ), can more effectively induce bronchodilation with potential additive effects of suppressing release of inflammatory mediators (Calzetta et al ., 2013; Franciosi et al ., 2013). Moreover, dual inhibition of PDE3 and PDE4 sensitized cells to long acting β 2 ‐adrenoceptor agonists (LABAs) and corticosteroid (ICS)/LABA combinations, in cell‐based models (BinMahfouz et al ., 2015), indicating that dual inhibition of PDE3 and PDE4 acted as an add‐on effect to LABAs and ICS/LABA combinations, to further enhance their therapeutic benefits (Giembycz and Maurice, 2014).…”