Synthesis and Optimization of a New Family of Type 3 17β-Hydroxysteroid Dehydrogenase Inhibitors by Parallel Liquid-Phase Chemistry

摘要: Type 3 17β-hydroxysteroid dehydrogenase (17β-HSD) transforms 4-androstene-3,17-dione (Δ4-dione) into the androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we performed parallel liquid-phase synthesis 3β-substituted androsterone (ADT) libraries (A−D) in good yields and average high-performance liquid chromatography (HPLC) purities 92−94%. The first library (A) 3β-amidomethyl-ADT derivatives (168 members), including two levels molecular diversity on amide (R1 R2), was synthesized with a method (method I) less time than classic chemistry method. screening A revealed that relatively small hydrophobic chains at R1 (5−8 carbons) substituents R2 (1−4 provided most inhibitors. In accordance these inhibition results, second (B) (56 members) generated very short using an improved based scavenger ...