In Vivo Characterization of GSK256066, a High-Affinity Inhaled Phosphodiesterase 4 Inhibitor

Abstract

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.

CHF6001 II: A Novel Phosphodiesterase 4 Inhibitor, Suitable for Topical Pulmonary Administration—In Vivo Preclinical Pharmacology Profile Defines a Potent Anti-Inflammatory Compound with a Wide Therapeutic Window

“…A direct estimate of the emetogenic activity in conscious ferrets (Kuss et al, 2003;Nials et al, 2011) was done by evaluating both vomiting and nausea-related behaviors. CHF6001 was completely emetogenic inactive up to the dose of 10 mmol/kg, confirming its low emetogenic potential.…”

The In Vitro Pharmacology of GS-5759, A Novel Bifunctional Phosphodiesterase 4 Inhibitor and Long Acting β2-Adrenoceptor Agonist

“…The therapeutic index for roflumilast is narrow because of dose-limiting nausea and emesis (Spina, 2008). Attempts to develop an inhaled PDE4 inhibitor have resulted in molecules with an improved side effect profile, while still being selective and potent (Chapman et al, 2010;Nials et al, 2011;TralauStewart et al, 2011). The combination of a bronchodilator with an anti-inflammatory agent as a treatment of COPD has been extensively discussed and is reviewed in Phillips and Salmon (2012).…”

A Perspective on Synthetic and Solid-Form Enablement of Inhalation Candidates

“…These include p38 mitogen-activated protein kinase inhibitors [201], histamine H3 antagonists [101], phosphodiesterase type 4 (PDE4) inhibitors [10][11][12], spleen tyrosine kinase inhibitors [13] and adenosine A 2A agonists [14,15]. A recent development has been the concept of a dual-pharmacology approach, whereby two pharmacophores are combined within one molecule.…”