ABHD12 has remained a challenging target for inhibitor development as there are no crystal structures available, number of known inhibitors is low and the existing MLN4924 side effects activity data are GDC-0879 limited. In order to find novel lead structures for selective inhibitors of recently discovered serine hydrolases, exploring the activity of natural compounds may offer valuable information for this developing process. For instance, plant-derived pentacyclic triterpenes such as betulinic, oleanolic and ursolic acid are interesting molecules as they all are bioactive and widespread in nature and their therapeutic potential is well documented see also reviews and references cited therein. In addition, their multi-targeting biological activity, low toxicity, easy availability, and core structure offering good starting point for chemical modifications, make triterpenoids appealing source for the drug discovery. Along this line, recent studies have revealed that triterpenes may include potential candidates for novel inhibitors of e.g. endocannabinoid hydrolases. Indeed, pristimerin has been shown to inhibit MAGL activity in in vitro studies. In another study, a mixture of a/b-amyrin was shown to reduce inflammatory and neuropathic hyperalgesia in mice through activation of the cannabinoid CB1 and CB2 receptors. Interestingly, despite their high affinity towards CB1R, the compounds failed to show any cannabimimetic effects in the tetrad test. In addition, a- and b-amyrin were reported to inhibit 2-AG-hydrolysis in pig brain homogenates. The molecular target of this action was not identified. Our preliminary screening efforts to identify novel serine hydrolase inhibitors among various chemical compounds revealed unexpectedly that ursolic acid was able to selectively inhibit ABHD12 with negligible effect on ABHD6 or MAGL activity. Inspired by this finding, we selected various commercial triterpenes/triterpenoids as well as recently reported betulin-based triterpenes for further evaluation. In this paper, we report the inhibitory activity of these compounds towards human ABHD12. Based on the activity data we have established preliminary structure-activity relationships and constructed the first pharmacophore model for betulin-based triterpenes. This model should prove useful in the discovery of novel lead structures for ABHD12 selective inhibitors. Although the triterpenoids typically interact with multiple protein targets, we witnessed unprecedented selectivity towards ABHD12 among the metabolic serine hydrolases, as activity-based protein profiling of mouse brain membrane proteome indicated that the representative ABHD12 inhibitors did not inhibit other serine hydrolases, nor did they target cannabinoid receptors. Pentacyclic triterpenes can be classified into three different groups: lupanes, oleananes and ursanes. Derivatives of triterpenes are called triterpenoids. In this study, commercially available triterpenes 1�C11 and triterpenoids 12�C15 were purchased from different chemical vendors and tested for their ability to inhibit hydrolase activity in lysates of HEK293 cells transiently overexpressing human ABHD12. The inhibition data are presented in Table 1. In the lupane series, an importance of a carboxyl group at position 17 was shown as betulinic acid had the highest inhibitory activity. However, lipophilicity differences should also be taken into consideration as the compound with the lowest logD also had the highest inhibitory activity. In the ursane series, similar effect of the carboxyl 
group at position 17 was observed as ursolic acid showed higher inhibition activity compared to a-amyrin that has a methyl group at this position. Asiatic acid, which has a primary hydroxyl group at the position 4, was completely devoid of activity, demonstrating the importance of this position for hABHD12 inhibition.