Oglemilast

Oglemilast Description:IC50: 2.5 nM (PDE4B) and 1.7 nM (PDE4D) [1]Among the emerging agents to treat COPD or asthma, phosphodiesterase 4 (PDE4) inhibitors have attracted particular attention. PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Oglemilast is an orally administered inhibitor drug which is touted as an important and novel therapeutic target for asthma and chronic obstructive pulmonary disease (COPD), also known as smoker's cough.
In vitro: Oglemilast (GRC-3886), a potent PDE4 inhibitor, inhibited PDE4 enzyme with an IC50 value of 1.4 nM and exhibited > 7,000-fold selectivity over other PDE (PDE1–11) families. In human whole blood assays, oglemilast inhibited LPS-induced TNFα production with an IC50 value of 190 nM and [2].
In vivo: Oglemilast oral treatment of rats blocked Lipopolysaccharide (LPS)-induced pulmonary neu-trophilia with an ID50 of 1.45 mg/kg. In ferrets, oglemilast neither induced emesis nor caused any behavioral changes associated with emesis at 100 mg/kg. Hence, oglemilast could represent a new generation of potent selective PDE4 inhibitor with significantly improved emetic side-effect profile [2].
Clinical trial: Glenmark Pharmaceuticals’ licensing partner, Forest Laboratories, announced that the Phase IIb results on Oglemilast did not show a statistically meaningful increase from the baseline compared to the placebo (dummy drug). The markets took to this badly and the stock was pummeled on the bourses.
Reference:
[1] Gorja DR, Mukherjee S, Meda CL, Deora GS, Kumar KL, Jain A, Chaudhari GH, Chennubhotla KS, Banote RK, Kulkarni P, Parsa KV, Mukkanti K, Pal M. Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors. Org Biomol Chem. 2013;11(13):2075-9.
[2] Vakkalanka SKVS, Balasubramaniam LA, Gharat LA, et al. The pharmacological and safety profile of a novel selective phosphodiesterase-4 (PDE4) inhibitor:GRC-3886. Eur Respir J 2004;24:1391

Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking?[Pubmed:18660832]

Br J Pharmacol. 2008 Oct;155(3):288-90.

PDE4 inhibitors have been in development as a novel anti-inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD-12-281 (aka GSK 842470), CDP840, CI-1018, D-4418, IC485, L-826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub-therapeutic or at the very bottom of the efficacy dose-response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many 'new(er)' PDE4 inhibitors in development are reported to have an improved therapeutic window including tetomilast, Oglemilast, apremilast, ONO 6126, IPL-512602 and IPL-455903 (aka HT-0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti-inflammatory activity of PDE inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 inhibitors to suppress inflammation still remains a viable concept.

Oglemilast (GRC 3886) is a potent and orally active phosphodiesterase-4 (PDE4) inhibitor with an IC50 of 0.5 nM for PDE4D3. Oglemilast inhibits pulmonary cell infiltration, including eosinophilia and neutrophilia in vitro and in vivo. Oglemilast has the potential for inflammatory airway diseases.

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