Cilomilast

Cilomilast, also known as SB-207499 or Ariflo, is a potent second generation inhibitor of type 4 phosphodiesterase (PDE4), an enzyme metabolizing cellular cyclic adenosine monophosphate (cAMP) which acts as a second messenger to disrupt the function of inflammatory cell and induce airway smooth muscle relaxation. Cilomilast is currently used for the treatment of chronic obstructive pulmonary disease (COPD) due to its strong anti-inflammatory activity as well as inhibitory effects against the release of neutrophil chemoattractants (such as tumor necrosis factor TNF- α, interleukin IL-8 and granulocyte-macrophage colony stimulating factor GM-CSF) and suppression of the recruitment of neutrophils into tissues and the LTB4 production.

Reference

M Profita, G Chiappara, F Mirabella, RCDi Giorgi, L Chimenti, G Costanzo, L Riccobono, V Bellia, J Bousquet, and A M Vignola. Effect of cilomilast (Ariflo) on TNF-α, IL-8, and GM-CSF release by airway cells of patients with COPD. Thorax 2003; 58: 573-579

Barry D. Zussman, Lisa J. Benincosa, Dawn M Webber, David j. Clark, Hugh Cowley, John Kelly, Robert D. Murdoch, James Upward, Peter Wyld, Andreas Port and Hermann Fuder. An overview of the pharmacokinetics of cilomilast (Ariflo), a new, orally active phosphodiesterase 4 inhibitor, in healthy young and elderly volunteers. J Clin Pharmacol 2001; 41: 950-958

Cilomilast enhances osteoblast differentiation of mesenchymal stem cells and bone formation induced by bone morphogenetic protein 2.[Pubmed:22706281]

Biochimie. 2012 Nov;94(11):2360-5.

A rapid and efficient method to stimulate bone regeneration would be useful in orthopaedic stem cell therapies. Rolipram is an inhibitor of phosphodiesterase 4 (PDE4), which mediates cyclic adenosine monophosphate (cAMP) degradation. Systemic injection of rolipram enhances osteogenesis induced by bone morphogenetic protein 2 (BMP-2) in mice. However, there is little data on the precise mechanism, by which the PDE4 inhibitor regulates osteoblast gene expression. In this study, we investigated the combined ability of BMP-2 and Cilomilast, a second-generation PDE4 inhibitor, to enhance the osteoblastic differentiation of mesenchymal stem cells (MSCs). The alkaline phosphatase (ALP) activity of MSCs treated with PDE4 inhibitor (Cilomilast or rolipram), BMP-2, and/or H89 was compared with the ALP activity of MSCs differentiated only by osteogenic medium (OM). Moreover, expression of Runx2, osterix, and osteocalcin was quantified using real-time polymerase chain reaction (RT-PCR). It was found that Cilomilast enhances the osteoblastic differentiation of MSCs equally well as rolipram in primary cultured MSCs. Moreover, according to the H89 inhibition experiments, Smad pathway was found to be an important signal transduction pathway in mediating the osteogenic effect of BMP-2, and this effect is intensified by an increase in cAMP levels induced by PDE4 inhibitor.

Repurposing human PDE4 inhibitors for neglected tropical diseases: design, synthesis and evaluation of cilomilast analogues as Trypanosoma brucei PDEB1 inhibitors.[Pubmed:25127163]

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4084-9.

A medicinal chemistry exploration of the human phosphodiesterase 4 (hPDE4) inhibitor Cilomilast (1) was undertaken in order to identify inhibitors of phosphodiesterase B1 of Trypanosoma brucei (TbrPDEB1). T. brucei is the parasite which causes African sleeping sickness, a neglected tropical disease that affects thousands each year, and TbrPDEB1 has been shown to be an essential target of therapeutic relevance. Noting that 1 is a weak inhibitor of TbrPDEB1, we report the design and synthesis of analogs of this compound, culminating in 12b, a sub-micromolar inhibitor of TbrPDEB1 that shows modest inhibition of T. brucei proliferation.

Comparison of the anti-inflammatory effects of Cilomilast, Budesonide and a p38 Mitogen activated protein kinase inhibitor in COPD lung tissue macrophages.[Pubmed:23148608]

BMC Pharmacol Toxicol. 2012 Nov 13;13:15.

Chronic Obstructive Pulmonary Disease (COPD) is a disease characterized by a largely irreversible airflow obstruction and a persistent, excessive inflammatory response. Alveolar macrophages (AMs) are increased in the lungs of COPD patients, and act as orchestrators of the inflammatory response, releasing a range of mediators to coordinate recruitment and activation of leukocytes. Attempts to treat the inflammatory component of COPD with anti-inflammatory drugs such as steroids has met with limited success. In this study, we compared the ability of the phosphodiesterase IV (PDEIV) inhibitor Cilomilast, the steroid Budesonide, and the p38 mitogen activated protein kinase inhibitor BIRB-796 to inhibit tumour necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) releases from AMs isolated from COPD lung transplant tissue. All studies were carried out with appropriate ethical approval and written, informed consent was obtained from each subject. Cilomilast had little effect on cytokine release from AMs. There was considerable variability in the responsiveness of AMs to Budesonide, with a subset of AMs responding poorly to Budesonide. BIRB-796 inhibited TNFalpha release from all AM donors, including those that responded poorly to steroids. Treatment with BIRB-796 and Budesonide together gave an additive decrease in TNFa release. These results suggest that a p38 inhibitor may provide advantages over existing anti-inflammatory treatments for COPD, either as an add-on to existing therapy, or to treat patients who respond poorly to steroids.

Cilomilast counteracts the effects of cigarette smoke in airway epithelial cells.[Pubmed:21382614]

Cell Immunol. 2011;268(1):47-53.

Cigarette smoke extracts (CSE) alter TLR4 expression and activation in bronchial epithelial cells. Cilomilast, a phosphodiesterase-4 inhibitor, inhibits cigarette smoke-induced neutrophilia. This study was aimed to explore whether Cilomilast, in a human bronchial epithelial cell line (16-HBE), counteracted CSE effects. In particular, TLR4 expression, IP-10 and IL-8 release, lymphocyte and neutrophil chemotactic activity and ERK and IkBa phosphorylation in CSE and LPS-stimulated 16-HBE were assessed. CSE increased TLR4 expression, reduced IP-10 release and lymphocyte chemotactic activity and increased IL-8 release and neutrophil chemotactic activity. Cilomilast reduced TLR4 expression, IL-8 release and neutrophil chemotactic activity as well as it increased IP-10 release and lymphocyte chemotactic activity. All these Cilomilast mediated effects were associated with a reduced ERK1/2 and with an increased IkBa phosphorylation. In conclusion, the present study provides compelling evidences that Cilomilast may be considered a possible valid therapeutic option in controlling inflammatory processes present in smokers.

Cilomilast(SB 207499; Ariflo) is a potent PDE4 inhibitor with IC50 of about 110 nM, has anti-inflammatory activity and low central nervous system activity.

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