(P146) CANNABINOID MEDICINAL CHEMISTRY HAS VAST IMPACT ON PHARMACOLOGY IN MOUSE AND RAT MODELS OF INFLAMMATORY BOWEL DISEASE (IBD)

Natural cannabinoids are experiencing a renaissance in pharmacological research. With over 400 studies reported on clinicaltrials.gov, cannabidiol (CBD) and cannabigerol (CBG) are among the most extensively studied. Despite the potential of cannabinoids, few drugs have been approved. Due to low oral bioavailability clinically investigated cannabinoids must be administered at remarkably high doses, which can lead to complications including severe hepatic impairment.

Recently, a rare THC molecule with a seven-term alkyl side chain was found to bind CB receptors up to 66 times more effectively than THC. From our previous work we determined the primary site of metabolism of CBG was at the hydroxyl sites. Consequently, we sought to explore Structure Activity Relationships (SAR) focusing on the alkyl side chain and the hydroxyl sites. To our knowledge, cannabinoid derivatives have not been specifically developed for targeting IBD.
Seventeen derivatives were characterized in vitro for their potential to inhibit pro-inflammatory cytokines. Subsequently, we screened 10 derivatives in a mouse model of Trinitrobenzenesulfonic Acid (TNBS)-induced colitis. While CBG was ineffective, we found two compounds—(1’R,2’R)-4-heptyl-6-methoxy-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1’,1’-biphenyl]-2-ol and (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-dimethoxy-5-pentylbenzene - DM350-P, and DM300 respectively—to be highly efficacious. Subsequently, in an Indomethacin-induced Crohn’s Disease (CD) model in rats, both DM300 and DM350-P were highly effective at reducing inflammation and necrosis in the small bowel when administered orally.  An oral rat pharmacokinetic (PK) study revealed that the derivatives had bioavailability up to 15 times higher than natural cannabinoids, as determined by the area under the plasma concentration versus time curve (AUC) calculation.

Additionally, we employed the BioMAP Diversity Plus panel of 12 human primary cell-based systems modeling complex human tissue and disease biology. The derivatives shared common threads in anti-inflammatory, immunomodulatory, and tissue remodeling activities. The BioMAP panel corroborated our in vivo data. DM350-P was the most active and potent, while DM300 was active with moderate potency.
These data support that DM300 and DM350-P may have potential to prevent NSAID induced gastrointestinal injury and treat IBD while presenting safer profiles than natural cannabinoids due to improved bioavailability. Our cannabinoid SAR studies have identified promising lead candidates derived from just two out of more than 130 known natural cannabinoids. While we plan to advance these candidates, extending our cannabinoid SAR research by utilizing AI-assisted design and learning, may establish a new paradigm for discovering orally available small molecules to treat IBD.