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A collaborative endeavor among ETH, Oregon Health & Science University, and Roche has led to the identification of novel CB2R inverse agonists. These compounds display exceptional binding affinity for CB2R and remarkable selectivity over CB1R, effectively reducing potential central nervous system side effects.

𝐒𝐲𝐧𝐭𝐡𝐞𝐭𝐢𝐜 𝐒𝐭𝐫𝐚𝐭𝐞𝐠𝐢𝐞𝐬 𝐟𝐨𝐫 𝐬𝐞𝐥𝐞𝐜𝐭𝐢𝐯𝐞 𝐂𝐁𝟐𝐑 𝐢𝐧𝐯𝐞𝐫𝐬𝐞 𝐚𝐠𝐨𝐧𝐢𝐬𝐭𝐬: 𝐂𝐡𝐞𝐦𝐀𝐈𝐑𝐒-𝐀𝐬𝐬𝐢𝐬𝐭𝐞𝐝 𝐑𝐨𝐮𝐭𝐞 𝐃𝐞𝐯𝐞𝐥𝐨𝐩𝐦𝐞𝐧𝐭

ChemAIRS focuses on the synthesis of these CB2R-selective inverse agonists, which are derived from the privileged scaffold of 𝐇𝐔-𝟑𝟎𝟖, a well-known CB2R agonist. The synthetic route commences with compound 3b, which was obtained via methylation of 3,5-dimethoxyphenylacetonitrile followed by treatment with phenyl lithium (Scheme 1). In the subsequent step, ChemAIRS proposed using a 𝐺𝑟𝑖𝑔𝑛𝑎𝑟𝑑 𝑟𝑒𝑎𝑔𝑒𝑛𝑡 to introduce an alkyl side chain to the ketone 3b, yielding racemic compound 4a. The conjugated alkene 4a was selectively reduced through hole-transfer catalysis to furnish 8b, which then underwent 𝐹𝑟𝑖𝑒𝑑𝑒𝑙-𝐶𝑟𝑎𝑓𝑡𝑠 𝑎𝑙𝑙𝑦𝑙𝑎𝑡𝑖𝑜𝑛 with verbenol derivative 8a, producing intermediate 9a. Hydroazidation of the alkene with TMSN3 and subsequent phthalimide deprotection via hydrazine unveiled the target molecule.

𝐀𝐥𝐭𝐞𝐫𝐧𝐚𝐭𝐢𝐯𝐞 𝐒𝐲𝐧𝐭𝐡𝐞𝐭𝐢𝐜 𝐒𝐭𝐫𝐚𝐭𝐞𝐠𝐲 𝐟𝐨𝐫 𝐂𝐁𝟐𝐑 𝐈𝐧𝐯𝐞𝐫𝐬𝐞 𝐀𝐠𝐨𝐧𝐢𝐬𝐭 𝐃𝐞𝐯𝐞𝐥𝐨𝐩𝐦𝐞𝐧𝐭

In this alternative route (Scheme 2), ChemAIRS suggested alkylating ketone 1b via reaction with iodide 1a. Introduction of the gem-dimethyl group was achieved by treatment of 2a with TiCl4 and AlMe3, affording 3a, which was then brominated and reacted with B(OMe)3 to yield arylboronic acid 7b.
On the other hand, N-Boc-protected allylic amine 6a was formed under 𝑀𝑖𝑡𝑠𝑢𝑛𝑜𝑏𝑢 𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛𝑠, and subsequent bromination yielded 7a. A 𝑆𝑢𝑧𝑢𝑘𝑖 𝑐𝑜𝑢𝑝𝑙𝑖𝑛𝑔 between 7a and arylboronic acid 7b afforded 8a. The final step of this method involved Boc deprotection to generate the target molecule, 𝑖𝑛 𝑐𝑜𝑛𝑡𝑟𝑎𝑠𝑡 𝑡𝑜 𝑝ℎ𝑡ℎ𝑎𝑙𝑖𝑚𝑖𝑑𝑒 𝑟𝑒𝑚𝑜𝑣𝑎𝑙 𝑎𝑠 𝑝𝑟𝑜𝑝𝑜𝑠𝑒𝑑 𝑖𝑛 𝑆𝑐ℎ𝑒𝑚𝑒 1.

In conclusion, the development of CB2 inverse agonists presents a promising avenue for therapeutic intervention in inflammatory and immune-related diseases. 𝑻𝒉𝒆 𝒔𝒚𝒏𝒕𝒉𝒆𝒕𝒊𝒄 𝒓𝒐𝒖𝒕𝒆𝒔 𝒉𝒊𝒈𝒉𝒍𝒊𝒈𝒉𝒕𝒆𝒅 𝒃𝒚 𝑪𝒉𝒆𝒎𝑨𝑰𝑹𝑺 𝒏𝒐𝒕 𝒐𝒏𝒍𝒚 𝒑𝒓𝒐𝒗𝒊𝒅𝒆 𝒆𝒇𝒇𝒊𝒄𝒊𝒆𝒏𝒕 𝒎𝒆𝒕𝒉𝒐𝒅𝒔 𝒇𝒐𝒓 𝒂𝒄𝒄𝒆𝒔𝒔𝒊𝒏𝒈 𝒕𝒉𝒆𝒔𝒆 𝒄𝒐𝒎𝒑𝒐𝒖𝒏𝒅𝒔 𝒃𝒖𝒕 𝒂𝒍𝒔𝒐 𝒓𝒆𝒗𝒆𝒂𝒍 𝒑𝒐𝒕𝒆𝒏𝒕𝒊𝒂𝒍 𝒑𝒊𝒕𝒇𝒂𝒍𝒍𝒔 𝒊𝒏 𝒕𝒉𝒆 𝒔𝒚𝒏𝒕𝒉𝒆𝒔𝒊𝒔, 𝒐𝒇𝒇𝒆𝒓𝒊𝒏𝒈 𝒗𝒂𝒍𝒖𝒂𝒃𝒍𝒆 𝒊𝒏𝒔𝒊𝒈𝒉𝒕𝒔 𝒇𝒐𝒓 𝒇𝒖𝒕𝒖𝒓𝒆 𝒐𝒑𝒕𝒊𝒎𝒊𝒛𝒂𝒕𝒊𝒐𝒏. Continued exploration of these pathways will enhance our understanding of CB2R modulation and its potential clinical applications.