Highly Potent 17β-HSD2 Inhibitors with a Promising Pharmacokinetic Profile for Targeted Osteoporosis Therapy.

Intracellular elevation of E2 levels in bone by inhibition of 17β hydroxysteroid dehydrogenase type 2 (17β-HSD2) without affecting systemic E2 levels is an attractive approach for a targeted therapy against osteoporosis, a disease which is characterized by loss of bone mineral density. Previously identified inhibitor A shows high potency on human and mouse 17β-HSD2, but poor pharmacokinetic properties when applied perorally in mice. A combinatorial chemistry approach was utilized to synthesize truncated derivatives of A, leading to highly potent compounds with activities in the low nanomolar to picomolar range.