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CB2 agonists
C4T Approaches

endocannabinoid system CB1
cannabinoid receptor 1 CB2
cannabinoid receptor 2 C4T S.C. a r.l.
monoacylglycerol lipase V.le della Ricerca FAAH
fatty acid amide hydrolase Scientifica snc, THC
Δ9- tetrahydrocannabinol c/o Università degli Studi CBD
cannabidiol di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 Endocannabinoid System
The cannabinoid system (ECS) has attracted pharmacologists interest for its potential as therapeutic targets for several diseases ranging from obesity to Parkinson's dis-ease and from multiple sclerosis to pain. The ECS is an ubiquitous signaling system involved in important regulatory functions, which consists of:  Cannabinoid receptors:1 CB1, CB2 and GPR55, the latter recently indicated as "type 3" cannabinoid receptor2 (CB3)  Endogenous ligands (endocannabinoids):3 the most bioactive are anandamide (AEA) and 2-arachidonylglycerol (2-AG), released on demand from phospholip-id precursors in both CNS and PNS  Protein transporters and enzymes involved in their synthesis, cell uptake and degradation:4 NAPE-PLD, DAGL, MAGL, FAAH and others. This system plays a critical role in many physiological processes such as learning and memory, appetite control, pain sensation, motor coordination, lipogenesis, modula- tion of immune response, and regulation of bone mass. Alterations in the endogenous cannabinoid system have been described in almost every category of disease. These changes can alternatively be protective or maladap- tive, such as producing antinociception in neuropathic pain or fibrogenesis in liver disease, making the system an attractive therapeutic target. C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 Cannabinoid Receptors
The CBRs belong to the seven transmembrane spanning (7TM)/G protein-coupled receptor (GPCRs) family and are perhaps the most abundant GPCRs expressed at high levels in many regions of the mammalian brain. CB receptors are expressed in both central and peripheral nervous system (CNS and PNS, respectively) where they are involved in the modulation of the several physio-logical events. CB1 is heterogeneously expressed at high levels in the central nervous system (CNS)
and in peripheral tissue (e.g., liver and adipocytes), while CB2 is localized mainly on
immune cells and microglia and is associated with immune function5 (Table 1).
The varying degree of selectivity of endogenous and exogenous cannabinoids for CB1 and CB2 receptors accounts for their various psychotropic and peripheral effects. G protein-coupled receptor 55 (GPR55) was recently proposed as a novel compo-nent of this system, putative CB3 receptor and it has attracted much attention , po- tentially explaining physiological effects that are non-CB1/CB2 mediated.6 Table 1: CB receptor localization and physiological pathway modulation
C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 Cannabinoids and Therapeutic Perspectives
It is widely accepted that non-endogenous compounds that target CB1 and/or CB2 receptors possess therapeutic potential for the clinical management of an ever growing number of disorders,7 including: Inflammatory and neuropathic pain Obesity and metabolic disorders Neurological diseases Cancer and others Just a few of these disorders are already treated with (9)-THC or nabilone, both CB1/CB2 receptor agonists (Table 2).
Table 2: CB1/CB2 agonists in pharmaceutical market.
Therapeutic Area/ Diseases
Chronic pain management Nabilone
Emesis and Anorexia: chemotherapy- Synthetic derivative of THC induced nausea and vomiting and for ano-rexia treatment in patients with AIDS Emesis and Anorexia: chemotherapy- Dronabinol
Medicinal product contain- induced nausea and vomiting and for ano- rexia treatment in patients with AIDS Nabiximols
Oromucosal mouth spray Neuropathic pain and spasticity in MS pa-tients containing THC e CBD Bedrocan
Pain in in patient with cancer, AIDS, MS Medicinal product based on THC and CBD There is now considerable interest in expanding the clinical applications of such agonists and also in exploiting CB2-selective agonists, peripherally restricted CB1/CB2 receptor agonists and CB1/CB2 antagonists and inverse agonists as medicines. Already numerous cannabinoid receptor ligands have been developed and their interactions with CB1 and CB2 receptors well characterized. C4T S.C. a r.l.
V.le della Ricerca Recently the possibility to target CB2 has emerged as an alternative for the treat- Scientifica snc, ment of a multitude of disparate diseases and pathological conditions,8 (i.e pain, atherosclerosis , cancer, inflammation). c/o Università degli Studi di Roma "Tor Vergata. In particular, the main advantage of targeting CB2 resides in the possibility to avoid Rome— Italy the psychotropic side effects characteristic of targeting CB1. Phone: 06-72594029 Fax: 06-72594031 Neuropathic Pain Persistent pains associated with inflammatory and neuropathic states are prevalent and debilitating diseases, which still remain without a safe and adequate treatment. Chronic pain represents a major health problem throughout the world, thus several companies and researchers have embarked on the search for new drugs and targets to treat the disease. Although CB1/CB2 agonists, synthetic derivatives of THC and CBD, are in market in several countries for the treatment of neuropathic pain, many severe psychotropic
effects are related to them due to central CB1 activation.9
From this perspective, CB2 selective agonists may have potential in the treatment of neuropathic pain as demonstrated by several pre-clinical studies in a variety of ro- dent models, avoiding the central side effects CB1 related.10 For example, local or sys- temic delivery of CB2 receptor agonists reversed hyperalgesia in models of both post-operative and neuropathic pain.11 In other studies, CB2 agonists reduced chronic con-striction injury (CCI)-induced sensitivity to light mechanical touch (allodynia) and re- versed allodynia caused by tight ligation of spinal nerves (SNL), spinal nerve transac- tion, brachial plexus avulsion partial sciatic nerve ligation (PSL), and others.12 In this contest, new selective CB2 agonists had so far reached clinical trials (see Table
3 for details).
Table 3: CB2 agonists in clinical trials for neuropathic pain management.
Kyowa Hakko Kirin GRC-10693
C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 Emesis, obesity and metabolic disorders Synthetic analogues of THC and CBD are today on the market in many countries as
anti-emetic drugs in chemotherapy-induced nausea and vomiting13 and for anorexia
treatment in patients with AIDS (see Table 2).
Based on orexigen effects of CB1, the inhibition of this receptor seemed to represent a new frontier for the pharmacological treatment of obesity, especially with the en- try into market in more than 62 countries of Rimonabant. However, the develop- ment of CB1 antagonist and inverse-agonists was discontinued due to their psychiat-ric side effects related to CB1 inhibition.14 Selective CB2 agonists, such as Hu-308, JWH-133 and JWH-015, instead, demonstrat- ed their efficacy in rat model of alcoholic hepatic steatosis by decreasing the liver/ body weight ratio and hepatic triglyceride content,15 representing a potential new alternative for treatment of some metabolic disorders. Neurodegenerative diseases The ECS system is emerging as a key regulator of neuronal cell fate and is able of con- ferring neuroprotection by the direct control of neurogenesis.16 1 is the main receptor of CNS, the presence of CB2 in the CNS, both in microglia and neuronal cells, suggests the possibility to use CB2 agonists to treat vari- ous neurological conditions, including Alzheimer's and Parkinson's diseases without psychotropic side effects.17 Cannabinoids have recently been shown to produce anti-tumor actions (reduction of inflammation, cell proliferation and cell survival properties) in different models of C4T S.C. a r.l.
cancer (i.e., breast, prostate and bone cancer). In particular, recent experimental date demonstrate the ability of CB2 agonists such as WIN55,212-2, CP,55940 and V.le della Ricerca Scientifica snc, JWH-133 to inhibit both cell proliferation and migration by CB2 activation, although a possible role for CB1 was not assessed.18 c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 C4T Project
Since 2007, C4T focused its activities on the study of ECS, in particular on the identifi-cation of CB2 modulators characterized by: Agonist or inverse agonist activity Chemical novelty – patentability Selectivity over CB1 and other members of the ECS Physical-chemical properties that make the compounds drug-like and po-tentially able to exert their effects at both peripheral and central system. In this field, C4T received awards and public funds from Ministero dell'Istruzione, dell'Università e della Ricerca (MIUR) and Regione Lazio (Filas-I DTB) Technology Platform for CB drug discovery To achieve the project aims, C4T developed a proprietary drug discovery platform for the identification of novel modulator of CB2 receptor, by integrating computational and synthetic C4T approaches with the Medium-Throughput Screening (MTS) per-formed by the group of Prof. Maccarrone (Univ. of Rome "Tor Vergata"). The platform includes:  CB receptor homology models validated by in vitro screening results  Max diverse/focused library generation  MTS on CB receptors t
Design and synthesis University of Teramo
Prof. M. Maccarrone
C4T S.C. a r.l.
In vitro screening and V.le della Ricerca Biochemical Characterizations Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 C4T3116 series: a novel class of CB2 selective agonists based on an innovative
scaffold was identified by in silico ap-
proaches and rational drug design studies.
The lead compound C4T 3116 represents
an ideal candidate for lead optimization.
The scaffold was identified by pharmaco-phore based virtual screening and a max diversity library was generated by explor-ing the three main scaffold chemical diver-sity points. By in silico studies, the C4T 3116 series shows:  a common CB2 binding mode  two common pharmacophore features  an undefined CB1 binding mode  Druglike properties  Potential good passive oral absorption (e.g., PSA in the range of 60-100 Å2) The most representative results of the identified class are reported below (Table 4).
The pool of compounds shows activity in the range 100-800 nM on CB2 and selectivi-
ty vs CB1 in according with the in silico studies. Furthermore, no inhibitory activity
towards MAGL and FAAH was observed up to a C4T agonist concentration of 100 M.
Table 4: Activity and selectivity results of C4T CB2-agonists
EC50-CB2 (nM)
EC50-CB1 (nM)
C4T S.C. a r.l.
(a) CB1 inverse-agonists V.le della Ricerca Scientifica snc, c/o Università degli Studi "Inverse agonists: From C4T 3116 Series, an inverse agonists focused library
di Roma "Tor Vergata. was obtained by a fine chemical modification of the prototypical structure in Rome— Italy one pharmacophore point. The experimental data confirmed the in silico hy- pothesis showing a different binding mode with respect to the agonists." Phone: 06-72594029 Fax: 06-72594031 C4T 3313 hit compound
By an original integrated ligand– structure-based approach, a second innovative
scaffold of CB2 agonist was identified (Table 5).
The hit compound C4T-3313 is an ideal candidate for the H2L :  low molecular weight  3 chemical diversity points  In silico known key interactions with CB2 residues  In silico nonspecific CB1 binding mode  Druglike properties. Table 5: Activity and selectivity results of C4T CB2– Hit
EC50-CB2 (M)
EC50-CB1 (M)
C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031

C4T Approaches
Design and synthesis Homology modeling of CBRs
CB1 e CB2 receptor 3D models were generated and validated by in vitro screening  Modeling of CB1 e CB2 receptors in their active and inactive state (CBR and CBR*, respectively) by using crystal structures of human b2-adrenergic receptor (pdb: 3d4s) and bovin rhodopsin (pdb: 1u19 and 1f88) as templates  Refinement of CBR* models on the crystal structure of bovin rhodopsin in complex with a peptide fragment of its G-protein transducin (pdb: 2X72). The 3D models were used in docking simulation for selecting compounds from the original virtual libraries and for studying the potential binding mode and selectivity of C4T 3116 Class compounds. Organic Synthesis
C4T S.C. a r.l.
 Study of synthetic feasibility of chemical scaffolds and parallel synthesis set-up V.le della Ricerca Scientifica snc,  Parallel synthesis of max diverse/focused libraries . c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 iological Screening Funnel (group of Prof. M. Maccarrone – UTV/UniTe) Binding assay
The affinity towards CB1 and CB2 was evaluated through "MultiScreenHTS 96 well
Plates for binding assays" by using membranes over-expressing CB receptors
(Millipore). The affinity, expressed as percentage of residual radioactivity of the ref-
erence compounds [3H] CP-55,940 (concentrations: 2.5 and 0.8 nM) in presence C4T
compound (concentration = 100 nM), is determined by the ability of the analyzed
compound to displace the specific binding of [3H] CP-55,940 (0.8 nM) to the recep-
tor (fmol of ligand / mg of protein).I In the experiments, non-specific binding was
determined in the presence of unlabeled CP-55,940 (concentration = 1 mM). The
compounds able to displace at least the 30% of the specific binding of CP-55940
were submitted to the activity determination via functional assays.
Funcional assays-[35S]GTPS (0.6 nM)
The determination of the activity of the C4T compounds is carried out by evaluating
the coupling of CBR/G-protein, by using the radioligand [35S] GTPS (0.6 nM),II in the
presence/absence of the reference standard CP-55,940
Fase 1: evaluation of the activity profile (agonist, antagonist or inverse-agonist) of C4T compounds at the two high concentrations of 10 M and 100 M in presence and in absence of the reference compound CP-55,940 Fase 2: determination of dose-response curve and EC50 value at eight different com-pound concentration (range: 10-4 -10-12 M). Selectivity profile over MAGL and FAAH

In addition, the potential inhibition of FAAHIII and MAGLIV activities has been deter-
mined as percentage of enzyme activity inhibition with respect to the control.
C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi I. Yao, B.B. et al., Br. J. Pharm., 2006, 149, 145-154;
di Roma "Tor Vergata. Rome— Italy II. Harrison, C. et al., Life Sci. 2003, 489-508;
III. Maccarrone, M. et al ., J. Cell Sci. 2005, 118, 4393-4404;
Phone: 06-72594029 IV. Dinh, T.P. et al., Proc. Natl. Acad Sci USA 99, 2002, 10819-10824.
Fax: 06-72594031 Partnership Opportunities
C4T is interested in: Project results licensing out Partnership for further development of C4T Hit/Lead compounds Technology Offer  A versatile drug discovery platform to drive and support a rational identifica- tion of novel CB modulators  Novel CB2 agonists - C4T3116 - CB2 selective agonist development (Lead optimization) - C4T3313 - CB2 selective agonist development (Hit to Lead). C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031 References
1 Matsuda et al. Nature 1990, 346, 561.
2. Topai et al., Curr Med Chem 2010, 17, 1411.
3. a) Okamoto et al. Vitam. Horm. 2009, 81, 1;
b) Ueda et al. Biofactors 2011, 37, 1.
4. Masini et al. Curr. Drug Target. 2012, Mar 19.
5.Maccarrone et al., Front. Behav. Neurosci. 2012, 6,9.
6 Ryberg et al. Br. J. Pharm. 2007, 152, 1092.
7. Pertwee. Br. J. Pharm. 2009, 156, 397.
8. Beltramo et al. J. Soc. Biol. 2009, 203, 99.
9. Murineddu et al. Recent Pat. CNS Drug Discov. 2012, 7, 4.
10. a) Brownjhon et al. Neuroscience 2012, 203, 180.
b) Hsieh GC et al., Br. J. Pharmacol. 2011, 162, 428 Update.
11 a) Romero-Sandoval et al., Anesthes. 2008, 108, 722.
b) Elmes et al., Eur. J. Neurosci. 2004, 20, 2311.
12. a) Yao et al., Pharmacol. Exp. Ther. 2009, 328, 141.
b) Leichsenring et al., Naunyn. Schmiedebergs Arch. Pharmacol. 2009, 379, 627.
c) Paszcuk et al., PLoS One 2011, 6:e24034.
13. Di Marzo, Pharmacol Reseach 2009, 60, 77.
14. Wilner et al. J Palliat Med, 2006, 9, 802.
Riether, Exp Opin Ther Pat 2012, 22, 495.
16. Gowran et al. CNS Neurosci Ther 2011, 17, 637.
Chunget al. 012, 1451, 110.
Guindon et al. Brit. J. Pharm. 2011, 163, 1447.
C4T S.C. a r.l.
V.le della Ricerca Scientifica snc, c/o Università degli Studi di Roma "Tor Vergata. Rome— Italy Phone: 06-72594029 Fax: 06-72594031


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