Pharmacological Profile of a Novel Phosphodiesterase 4 Inhibitor, 4-(8-Benzo[1,2,5]oxadiazol-5-yl-[1,7]naphthyridin-6-yl)-benzoic Acid (NVP-ABE171), a 1,7-Naphthyridine Derivative, with Anti-Inflammatory Activities

Abstract

We investigated the pharmacology of a new class of phosphodiesterase 4 (PDE4) inhibitor, 6,8-disubstituted 1,7-naphthyridines, by using 4-(8-benzo[1,2,5]oxadiazol-5-yl- [1,7]naphthyridin-6-yl)-benzoic acid (NVP-ABE171) as a representative compound and compared its potency with the most advanced PDE4 inhibitor, undergoing clinical trials, Ariflo [cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexanecarboxylic acid)]. NVP-ABE171 inhibited the activity of phosphodiesterase 4A, 4B, 4C, and 4D with respective IC 50 values of 602, 34, 1230, and 1.5 nM. Ariflo was about 40 times less potent. In human cells, NVP-ABE171 inhibited the eosinophil and neutrophil oxidative burst, the release of cytokines by T cells, and the tumor necrosis factor-␣ release from monocytes, in the nanomolar range. Ariflo presented a similar inhibition profile but was 7 to 50 times less potent. In BALB/c mice challenged with lipopolysaccharide, NVP-ABE171 inhibited the airway neutrophil influx and activation with an ED 50 in the range of 3 mg/kg. Ariflo was inactive up to a dose of 10 mg/kg. In ovalbumin sensitized Brown Norway rats, NVP-ABE171 inhibited the lipopolysaccharide-induced airway neutrophil influx and activation (ED 50 of 0.2 mg/kg) and the ovalbumin-induced airway eosinophil influx and activation (ED 50 of 0

Phosphodiesterase Type 4 Inhibitors Cause Proinflammatory Effects in Vivo

“…Treatment with roflumilast and piclamilast caused a reduction of neutrophil numbers in the BAL, a finding that agrees with published data. In mice (Corbel et al, 2002), treatment with piclamilast (assessed from 1 to 30 mg/kg) or NVP-ABE171 (Trifilieff et al, 2002) reduced BAL neutrophil numbers. Meanwhile in rats, inhibition of BAL neutrophilia was observed using cilomilast, SCH 351591, NVP-ABE171, rolipram, and AWD 12-281 (Escofier et al, 1999;Spond et al, 2001;Billah et al, 2002;Trifilieff et al, 2002;Kuss et al, 2003).…”

“…In mice, PDE 4 inhibitors have been shown to inhibit neutrophil numbers, tumor necrosis factor (TNF)-␣, transforming growth factor-␤ levels, and matrix metalloproteinase-9 activity in the bronchoalveolar lavage (BAL) (Corbel et al, 2002). In other experiments, PDE 4 inhibitors demonstrated suppression of lung myeloperoxidase activity, serum TNF-␣ levels (Miotla et al, 1998), BAL neutrophilia, and lymphocyte numbers (Trifilieff et al, 2002). Several PDE 4 inhibitors have also been demonstrated to be effective in rat models.…”

“…Several PDE 4 inhibitors have also been demonstrated to be effective in rat models. Studies have shown inhibition of neutrophil numbers (Spond et al, 2001;Billah et al, 2002;Trifilieff et al, 2002;Kuss et al, 2003) and neutrophil activation in BAL (Trifilieff et al, 2002). In guinea pigs, rolipram treatment was shown to completely reverse the bronchoconstriction produced by chronic treatment with LPS (Toward and Broadley, 2002).…”

Potency and Specificity of the Pharmacological Action of a New, Antiasthmatic, Topically Administered Soft Steroid, Etiprednol Dicloacetate (BNP-166)

“…Although asthma does not exist as a natural disease among animals, several animal models are available in which it is possible to demonstrate the pharmacological action of new antiasthmatic drug candidates (Szelenyi, 2000). Ovalbumin-sensitized and challenged Brown Norway rat is a widely used animal model in the development of agents with antiasthmatic properties (Huang et al, 2002;Trifilieff et al, 2002). Allergic challenge in this animal causes extensive inflammation in the lung with characteristic increase in the number of eosinophils and mucus-producing goblet cells and in the extent of perivascular edema (Schneider et al, 1997;Taylor et al, 1997).…”

Drugs in Clinical Development for Chronic Obstructive Pulmonary Disease

“…In vitro, CGH 2466 inhibited the enzymes PDE4 and p38 MAP kinase, and functioned as an antagonist at adenosine A2b receptors, with IC 50 values of 40, 95 and 63 nmol/l, respectively. In vivo, intranasal CGP 2466 inhibited both neutrophilic (induced by lipopolysaccharide) and eosinophilic (induced by ovalbumin) lung inflammation in mice, with ED 50 values in the range of 1–5 mg/kg [43]. …”