Synthesis of 17β-hydroxysteroid dehydrogenase type 10 steroidal inhibitors: Selectivity, metabolic stability and enhanced potency

17beta-Hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) is the only mitochondrial member of 17 beta-HSD family. This enzyme can oxidize estradiol (E2) into estrone (E1), thus reducing concentration of this neuroprotective steroid. Since 17 beta-HSD10 possesses properties that suggest a possible role in Alzheimer's disease, its inhibition appears to be a therapeutic strategy. After we identified the androsterone (ADT) derivative 1 as a first steroidal inhibitor of 17 beta-HSD10, new analogs were synthesized to increase the metabolic stability, to improve the selectivity of inhibition over 17 beta-HSD3 and to optimize the inhibitory potency. From six D-ring derivatives of 1 (17-C = O), two compounds (17 beta-H/17 alpha-OH and 17 beta-OH/17aC CH) were more metabolically stable and did not inhibit the 17 beta-HSD3. Moreover, solid phase synthesis was used to extend the molecular diversity on the 3b-piperazinylmethyl group of the steroid base core. Eight over 120 new derivatives were more potent inhibitors than 1 for the transformation of E2 to E1, with the 4-(4-trifluoromethyl-3-methoxybenzyl)piperazin-1-ylmethyl-ADT (D-3,7) being 16 times more potent (IC50 = 0.14 mM). Finally, D-ring modification of D-3,7 provided 17 beta-OH/17 alpha-C CH derivative 25 and 17 beta-H/17 alpha-OH derivative 26, which were more potent inhibitor than 1 (1.8 and 2.4 times, respectively). (C) 2020 Elsevier Masson SAS. All rights reserved.

Automated summary

17beta-Hydroxysteroid dehydrogenase type 10 (17 beta-HSD10) is a mitochondrial enzyme that can oxidize estradiol (E2) into estrone (E1). By synthesizing new derivatives, more potent inhibitors of 17 beta-HSD10 were found, which could be potential therapeutic strategies for Alzheimer's disease.