Design, chemical synthesis, and biological evaluation of novel triazolyl analogues of taranabant (MK-0364), a cannabinoid-1 receptor inverse agonist

Being obese has various health problems that are related to type 2 diabetes mellitus, cardiovascular disease, hypertension, hyperlipidemia, and fibrinolytic abnormalities. Merckʹs taranabant (MK-0364), a CB1R inverse agonist, is currently in Phase 3 clinical trials, and is being actively pursued by Merck toward obesity market. Merck intends to file for FDA approval of taranabant in 2008. In order to increase solubility and potency of taranabant, or even possibly improve safety, novel triazole analogues of taranabant have been designed and synthesized. We introduced a pivotal asymmetric center via the Evans chiral auxiliary methodology and set up 1,2,4-triazole via substitution of α-bromoketone. Subsequently, diastereoselective reduction was accomplished to install adjacent essential asymmetric center. This method allowed us to prepare readily sub-gram scale of the target compounds in a convenient way. The synthesized analogues were subjected to biological evaluation involving cannabinoid CB1 receptor binding affinity. While the parent taranabant bears highly potent binding affinity to cannabinoid CB1 receptor, neither of the analog structures improved CB1 receptor binding affinities.