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 μM) and RPL565 (10 μM) (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 α release from human monocytes [IC50; 0.52 μM (0.38-0.69) and 0.25 μM (0.18-0.35), respectively] and proliferation of human mononuclear cells to phytohemagglutinin [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) 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.
Footnotes
-
This work was supported by Vernalis Plc.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.105.099192.
-
ABBREVIATIONS: PDE, phosphodiesterase; MKS492, 8-amino-3,7-dihydro-7-(2-methoxyethyl)-1,3-dimethyl-1H-purine-2,6-dione; 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; RPL565, 6,7-dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one; K-H, Krebs-Henseleit solution; EFS, electrical field stimulation; BAL, bronchoalveolar lavage; EPO, eosinophil peroxidase; EB, Evans blue; TNF, tumor necrosis factor; LPS, lipopolysaccharide; DMSO, dimethyl sulfoxide; PHA, phytohemagglutinin; ANOVA, analysis of variance; CDP840, R-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine; RP73401, 3-(cyclopentyloxy)-N-(3,5-dichloro-4-pyridyl)-4-methoxybenzamide; AWD 12-281, N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide; Cl-930, 3(2H)-pyridazinone-4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methylmonohydrochloride; NVP-ABE171, 4-(8-benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic acid; YM976, 4-(3-chlorophenyl)-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one; Ro 20-1724, 4-3(Butoxy-4-methoxybenzyl)imidazolidin-2-one.
- Received December 5, 2005.
- Accepted May 4, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|