Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-, an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC 50 3.2 pM; steady-state IC 50 Ͻ0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC 50 390 pM), tofimilast (IC 50 1.6 nM), and cilomilast (IC 50 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor ␣ production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC 50 (compared with IC 50 values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC 50 . GSK256066 was highly selective for PDE4 (Ͼ380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and Ͼ2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (Ͼ17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED 50 values of 1.1 g/kg (aqueous suspension) and 2.9 g/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED 50 9.3 g/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease.

1 The anti-tussive eects, of the local anaesthetic, lidocaine and carcainium chloride (RSD931) have been investigated in guinea-pigs and rabbits. 2 Pre-treatment of guinea-pigs with aerosols of lidocaine or RSD931 at 0.1, 1.0 and 10 mg ml 71 reduced the number of citric acid-induced coughs by 9.3, 32.6 and 40.9% (P40.05) for lidocaine and by 25.3% (P40.05), 40.4% (P40.05) and 97.6% (P50.01) for RSD931, respectively and increased the latency to onset of cough at 10.0 mg ml 71 only. In addition, RSD931 at 10 mg ml 71 reduced citric acid-evoked cough responses in rabbits (with prior exposure to ozone at 3 p.p.m. for 1 h) from 22.1+5.1 to 2.7+0.9 coughs (P50.01). ) signi®cantly (P50.05 ± 50.01) reduced the spontaneous and histamineevoked discharges in Ad-®bres originating from airway, rapidly adapting stretch receptors (RARs) without aecting histamine-evoked bronchoconstriction. Lidocaine at 10.0 mg ml 71 also signi®cantly (P50.05) inhibited the spontaneous and histamine-induced discharges of RARs without aecting histamine-evoked bronchoconstriction. 5 Aerosols of RSD931 (10.0 mg ml 71 ) caused a transient, but signi®cant (P50.05), activation of pulmonary C-®bre endings 2.5 min after administration started. RSD931 had no signi®cant (P40.05) eects on discharges in bronchial C-®bres originating from bronchial C-®bre endings, capsaicin-evoked discharges of either pulmonary or bronchial C-®bre endings or on capsaicinevoked bronchoconstriction. In contrast, lidocaine (10.0 mg ml 71 ) signi®cantly (P50.05) inhibited spontaneous and capsaicin-induced discharges in both pulmonary and bronchial C-®bres respectively. Lidocaine also signi®cantly (P50.05) reduced capsaicin-evoked bronchoconstriction. 6 These studies suggest that the anti-tussive actions of RSD931 are mediated via inhibition of discharges in Ad-®bres originating from airway RARs. The mechanism of action of RSD931 is distinct from that of the local anaesthetic lidocaine and RSD931 may represent a novel class of antitussive agent.

Oral phosphodiesterase (PDE) 4 inhibitors have demonstrated clinical efficacy in chronic obstructive pulmonary disease and asthma. Preclinical and clinical investigation of inhaled PDE4 inhibitors is ongoing. 6-({3-[(Dimethylamino)carbonyl]phenyl}-sulfonyl)-8-methyl-4-{[3-methyloxy)phenyl]amino}-3-quinolinecarboxamide (GSK256066) is an exceptionally high-affinity and selective inhibitor of PDE4 designed for inhaled delivery. The aim of these studies was to investigate the potency, duration of action, and therapeutic index of GSK256066 in animal models of pulmonary inflammation. The effects of intratracheally administered GSK256066 were investigated in rat lipopolysaccharide (LPS)-and ovalbumin (OVA)-induced models of acute pulmonary inflammation. In some studies, fluticasone propionate (FP) was included as a comparator. The therapeutic index (anti-inflammatory effect versus emesis) of GSK256066 was studied in ferrets where acute pulmonary inflammation was induced with inhaled LPS. In rats, GSK256066 and FP caused significant (p Ͻ 0.05) inhibition of LPS-induced pulmonary neutrophilia. The duration of action of GSK256066 at 10 ϫ ED 50 dose (10 g/kg) was 12 h. GSK256066 and FP also inhibited LPS-induced increases in exhaled nitric oxide (ED 50 35 and 92 g/kg, respectively). In addition, GSK256066 inhibited pulmonary eosinophilia in rats exposed to OVA (ED 50 0.4 g/kg). In ferrets, inhaled GSK256066 inhibited LPS-induced pulmonary neutrophilia (ED 50 18 g/kg), and no emetic episodes were observed. Thus, GSK256066 may have an improved therapeutic index compared with oral PDE4 inhibitors, e.g., cilomilast and roflumilast. In summary, GSK256066 demonstrates potent and long-lasting anti-inflammatory effects in animal models of pulmonary inflammation and does not induce emetic episodes in ferrets. GSK256066 has potential as an inhaled therapeutic for the treatment of asthma and chronic obstructive pulmonary disease.

No abstract