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Use of adenine-derived compounds for the treatment of systemic lupus erythematosus (sle) rare disease




Lupus, adenine, drug in vivo

Statut des brevets

French patent application n°FR0601958 filed on March 6th, 2006 and entitled “Traitement du lupus érythémateux disséminé (LED) par les inhibiteurs de PDE4”


Sylviane MULLER

Statut commercial

Exclusive or non-exclusive licenses


Lanoratoire de Biophotonique et Pharmacologie , (LBP, UMR7213), Illkirch, France.



Since the eighties, we have been collaborating with JJ Bourguignon (University of Strasbourg) performing structure-activity relationships on purified PDE1 to PDE5 (based on rolipram and trequinsin structures) to conceive specific PDE4 inhibitors (>1000 original compounds) and we have studied PDE implications in intracellular signalling in cardiovascular function and more recently in angiogenesis.  Some findings were patented by Neuro3D/CNRS/University and lastly sold to Via Pharmaceuticals Inc., San Francisco, U.S.A. Among the not patented and optimized PDE4 inhibitors compounds, we have studied NCS 613 and its analogues as anti-inflammatory drugs. Therefore, in collaboration with Sylviane Muller, we established adenine analogues, and in particular NCS 613, as promising treatment for systemic lupus erythematosus (SLE) a rare diseases. Our latest results have shown encouraging in vivo effects on a mouse model.


SLE is a rare disease with a high polymorphism and multiple origins. The invention relates to the use of adenine-derived compounds, for the treatment of SLE. These original compounds are  specific and potent inhibitors of the PDE4 family enzymes which are implicated in inflammation. They can also be used in combination with a non steroid anti-inflammatory compound, a synthetic antimalarial compound, a corticoid compound or an immunosupressor.


NCS 613 is an adenine-derived molecule of low molecular weight (pKa<1.7, Log D7.4=3.78±0.03) that is active in vivo per os. This compound, given i. p. (30 µg/mouse, i.e. 1.5 mg/kg), protects mice from lupus disease progression (PlosOne 2012,) by decreasing proteinuria, anti-double stranded DNA antibodies and TNFα secretions and protecting kidney from nephropathy in which renal PDE4 activity is significantly increased when compared with control animals. Consequently, NCS 613 increases significantly the survival rate of MRL/lpr mice (SLE model) (p<0.005, in comparison with non treated mice). Furthermore, this compound decreases ex vivo basal and LPS-induced TNFα secretions from SLE and rheumatoid arthritis (RA) patient PBMCs.


The application of this invention concerns a drug for the treatment of SLE. The etiology remains elusive and the manisfestations are polymorphic classifying each form in the categoty of rare diseases. Currently, no specific treatment exists. An average of 15-50 out of 100.000 people is affected by SLE each year among northern Europeans to more than 200 cases per 1,000,000 people among black people (Compared to an average of 400-800 out of 100,000 people is affected by RA). Further, our results and patented technology broadens the use of our adenine analogues for the treatment of auto-immune diseases.

DEVELOPMENT STAGE: Pre-clinical data

In vitro assays :

NCS 613 is 12,380 fold more active than theophylline, 3214 fold more active than pentoxifylline and 18 fold more active than denbufylline as PDE4 inhibitor with an IC50 of 0.042 µM toward cAMP degradation by vascular purified PDE4.
– When compared to their effects on PDE5 activity (specific for cGMP and target for Viagra®), NCS 613 is 112 fold selective for PDE4, whereas theophylline similarly inhibits PDE4 and PDE5, pentoxifylline is 2 fold less potent on PDE4 and denbufylline is only 7 fold selective for PDE4.
NCS 613 (10 µM) inhibits by 70% antigen-induced histamine release by rat peritoneal mast cells, whereas rolipram (10 µM) decreases it only by 30%.
– NCS 613 inhibits fMLP-stimulated arachidonate acid (IC50= 1.99 µM) and LPS-stimulated TNFa (IC50= 0.018 µM) releases from human mononuclear cells.
– NCS 613 (10 µM) decreases ex vivo basal and LPS-induced TNFα secretions from SLE, and RA and Sjörgren syndrom (SS) patient PBMCs.
NCS 613 (10 µM) exhibits anti-inflammatrory effects on PBMCs from lupus patients by inhibiting p38 MAPK and NFk-B signalling pathway while reducing proinflammatory cytokine production (Can J Physiol Pharmac 2013,91:353-361)
– NCS 613 dose dependently (1, 10 and 30 mg/kg per os) inhibits the recruitment of neutrophils in the bronchoalveolar lavage fluid of mice exposed to endotoxin via aerosol and inhibits antigen-induced broncho constriction in guinea pig (0.1, 1 and 10 mg/kg per os) with an ED50 of 0.23 mg/kg being 100 fold more potent than theophylline.
– NCS 613 at 30 mg/kg i.v. in rat , in opposite to RP 73401, does not increase basal acid neither pentagastrin-stimulated acid secretion, suggesting that NCS 613 may produce fewer gastrointestinal side effects than second-generation PDE4 inhibitors.
NCS 613  given 3 times every 2 weeks and the last time 4 weeks later to 5 week-old MRL/lpr mice (at 30 µg/mouse i.e. 1.5 mg/Kg i.v.) significantly protects against SLE disease progression by decreasing proteinuria, anti-double stranded DNA antibodies and TNFα secretion and potently increases the mouse survival rate (at 30 weeks, 50% of NCS 613 treated mice were still alive, p<0.005) in comparison with non treated mice, whereas the survival rate of mice treated with pentoxifylline (100 µg/mouse) or denbufylline (100 µg/mouse) was not significantly changed.

Toxicity data :

NCS 613 given by i.v. at 1 µg or 10 µg, 3 times every 2 weeks,  to BALB/c mice which were observed for 40 days,  did not induced either weight changes or lung, kidney, liver and spleen alterations.

For further information, please contact us (Ref 00472-01)

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