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

Abstract 17beta-Hydroxysteroid dehydrogenase type 10 (17β-HSD10) is the only mitochondrial member of 17β-HSD family. This enzyme can oxidize estradiol (E2) into estrone (E1), thus reducing concentration of this neuroprotective steroid. Since 17β-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 17β-HSD10, new analogs were synthesized to increase the metabolic stability, to improve the selectivity of inhibition over 17β-HSD3 and to optimize the inhibitory potency. From six D-ring derivatives of 1 (17-C=O), two (17β-H/17α-OH and 17β-OH/17α-C≡CH) were more metabolically stable and did not inhibit the 17β-HSD3. Moreover, solid phase synthesis was used to extend the molecular diversity on the 3β-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 μM). Finally, D-ring modification of D-3,7 provided 17β-OH/17α-C≡CH derivative 25 and 17β-H/17α-OH derivative 26, which were more potent inhibitor than 1 (1.8 and 2.4 times, respectively).