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Development of CB2 agonists and FAAH inhibitors and their use in IBD

The CB2 receptor is a potential therapeutic target for various diseases from non-alcoholic steatohepatitis to multiple sclerosis and cancer. Unlike CB1 receptor, its activation did not cause psychotropic effects. Its therapeutic potential in IBD (Inflammatory Bowel Disease) is clearly established. Susceptibility of CB2 knockout mice with colitis and decrease in the intensity of colitis following the administration of CB2 agonists have been demonstrated by several groups which definitively established the proof of concept. In addition, the analgesic effect of selective CB2 agonists has been demonstrated in different models of chronic pain with an inflammatory or neuropathic origin. More specifically, our team showed an analgesic effect of a CB2 agonist in a model of visceral pain. Due to their ability to inhibit both inflammation and abdominal pain, CB2 agonists have a dual interest in the treatment of IBD.

Thus, our goal was to develop new selective CB2 receptor agonists. Six chemical series have been developed from a first series of CB2 agonists identified and a three-dimensional model of the CB2 receptor. Two chemical series have been patented by the University of Lille 2. The results have showed an anti-inflammatory effect for ten compounds after an IP or oral administrations. A transfer to the “SATT Nord de France” of this project was obtained in order to better understand the valorization aspects of the patented chemical series.

On the other hand, in parallel to this project, we have also developed compounds that specifically inhibit the FAAH enzyme activity (Fatty Acid Amide Hydrolase). FAAH hydrolyzes N-acetyl-ethanolamides (NAES) in fatty acids and plays a central role in the degradation of endocannabinoids. Several studies underline the importance of this target in IBD. Thus, anandamide (AEA) has a protective effect against inflammation. In addition, it was shown that FAAH-KO mice are protected against DNBS-induced colitis and that inhibitors of FAAH (URB597) were able to reduce intestinal inflammation. In this context, we have synthesized new FAAH inhibitors and also validated this concept by showing potent anti-inflammatory activity of these inhibitors against colitis.

In conclusion, the innovative aspect of this project is based on the fact that none of CB2 selective ligands and FAAH inhibitors is currently in development for the treatment of IBD. The scientific benefits of the project are important since it should lead to the discovery of the first anti-inflammatory and antinociceptive molecule in the intestine, with a very promising additional therapeutic potential in many inflammatory diseases (dermatitis, multiple sclerosis ...) and pain.

Publication

1. El Bakali J, Muccioli GG, Body-Malapel M, Djouina M, Klupsch F, Ghinet A, Barczyk A, Renault N, Chavatte P, Desreumaux P, Lambert DM, Millet R. Conformational Restriction Leading to a Selective CB2 Cannabinoid Receptor Agonist Orally Active Against Colitis. ACS Med Chem Lett. 2014 Dec 4;6(2):198-203. doi: 10.1021/ml500439x.

2. R. Millet, J. El Bakali,  M. Body-Malapel, N. Renault, G.G. Muccioli, P. Chavatte, P. Desreumaux, D.M. Lambert. 1,4-Dihydropyridines derivatives and their uses. Brevet Internationale (2010) déposé le 19 Mai 2010, WO 2010133973 A1

3. R. Millet, J. El Bakali, P. Chavatte, M. Body-Malapel, P. Desreumaux. Dérivés de 3,5-dihydro-2H-pyrazolo[4,3-c]pyrid-3-one et leur utilisation. Brevet Français déposé en 12 juin 2014, FR 14 55322.

4. Leleu-Chavain N, Desreumaux P, Chavatte P, Millet R. Therapeutical potential of CB₂ receptors in immune-related diseases. Curr Mol Pharmacol. 2013 Nov;6(3):183-203. Review.

5. Tourteau A, Leleu-Chavain N, Body-Malapel M, Andrzejak V, Barczyk A, Djouina M, Rigo B, Desreumaux P, Chavatte P, Millet R. Switching cannabinoid response from CB(2) agonists to FAAH inhibitors. Bioorg Med Chem Lett. 2014 Mar 1;24(5):1322-6. doi: 10.1016/j.bmcl.2014.01.056.

6. Tourteau A, Andrzejak V, Body-Malapel M, Lemaire L, Lemoine A, Mansouri R, Djouina M, Renault N, El Bakali J, Desreumaux P, Muccioli GG, Lambert DM, Chavatte P, Rigo B, Leleu-Chavain N, Millet R. 3-Carboxamido-5-aryl-isoxazoles as new CB2 agonists for the treatment of colitis. Bioorg Med Chem. 2013 Sep 1;21(17):5383-94. doi: 10.1016/j.bmc.2013.06.010.

7. Leleu-Chavain N, Biot C, Chavatte P, Millet R. From cannabis to selective CB2R agonists: molecules with numerous therapeutical virtues. Med Sci (Paris). 2013 May;29(5):523-8. doi: 10.1051/medsci/2013295016.

8. Renault N, Laurent X, Farce A, El Bakali J, Mansouri R, Gervois P, Millet R, Desreumaux P, Furman C, Chavatte P. Virtual screening of CB(2) receptor agonists from bayesian network and high-throughput docking: structural insights into agonist-modulated GPCR features. Chem Biol Drug Des. 2013 Apr;81(4):442-54. doi: 10.1111/cbdd.12095.

9.  Gembus V, Furman C, Millet R, Mansouri R, Chavatte P, Levacher V, Brière JF. Scaffold hopping strategy toward original pyrazolines as selective CB₂ receptor ligands. Eur J Med Chem. 2012 Dec;58:396-404. doi: 10.1016/j.ejmech.2012.10.031.

10. El Bakali J, Gilleron P, Body-Malapel M, Mansouri R, Muccioli GG, Djouina M, Barczyk A, Klupsch F, Andrzejak V, Lipka E, Furman C, Lambert DM, Chavatte P, Desreumaux P, Millet R. 4-Oxo-1,4-dihydropyridines as selective CB₂ cannabinoid receptor ligands. Part 2: discovery of new agonists endowed with protective effect against experimental colitis. J Med Chem. 2012 Oct 25;55(20):8948-52. doi: 10.1021/jm3008568.

11. Leleu-Chavain N, Body-Malapel M, Spencer J, Chavatte P, Desreumaux P, Millet R. Recent advances in the development of selective CB(2) agonists as promising anti-inflammatory agents. Curr Med Chem. 2012;19(21):3457-74. Review.

12. Andrzejak V, Muccioli GG, Body-Malapel M, El Bakali J, Djouina M, Renault N, Chavatte P, Desreumaux P, Lambert DM, Millet R. New FAAH inhibitors based on 3-carboxamido-5-aryl-isoxazole scaffold that protect against experimental colitis. Bioorg Med Chem. 2011 Jun 15;19(12):3777-86. doi: 10.1016/j.bmc.2011.04.057.

13. El Bakali J, Muccioli GG, Renault N, Pradal D, Body-Malapel M, Djouina M, Hamtiaux L, Andrzejak V, Desreumaux P, Chavatte P, Lambert DM, Millet R. 4-Oxo-1,4-dihydropyridines as selective CB2 cannabinoid receptor ligands: structural insights into the design of a novel inverse agonist series. J Med Chem. 2010 Nov 25;53(22):7918-31. doi: 10.1021/jm100286k.

14. Stern E, Muccioli GG, Bosier B, Hamtiaux L, Millet R, Poupaert JH, Hénichart JP, Depreux P, Goossens JF, Lambert DM. Pharmacomodulations around the 4-oxo-1,4-dihydroquinoline-3-carboxamides, a class of potent CB2-selective cannabinoid receptor ligands: consequences in receptor affinity and functionality. J Med Chem. 2007 Nov 1;50(22):5471-84.

15.  Stern E, Muccioli GG, Millet R, Goossens JF, Farce A, Chavatte P, Poupaert JH, Lambert DM, Depreux P, Hénichart JP. Novel 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives as new CB2 cannabinoid receptors agonists: synthesis, pharmacological properties and molecular modeling. J Med Chem. 2006 Jan 12;49(1):70-9.