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

• Published in: Journal of medicinal chemistry 2002-01, Vol.45 (3), p.640-653
• Main Authors: Maltais, René, Luu-The, Van, Poirier, Donald
• Format: Article
• Language: English
• Subjects: 17-Hydroxysteroid Dehydrogenases - antagonists & inhibitors; 17-Hydroxysteroid Dehydrogenases - chemistry; Androstanes - chemical synthesis; Androstanes - chemistry; Androstanols - chemical synthesis; Androstanols - chemistry; Animals; Antineoplastic agents; Biological and medical sciences; Cell Division - drug effects; Chromatography, High Pressure Liquid; Combinatorial Chemistry Techniques; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Female; General aspects; Medical sciences; Pharmacology. Drug treatments; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010286y

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 of 3β-substituted androsterone (ADT) libraries (A−D) in good yields and average high-performance liquid chromatography (HPLC) purities of 92−94%. The first library (A) of 3β-amidomethyl-ADT derivatives (168 members), including two levels of molecular diversity on the amide (R1 and R2), was synthesized with a parallel liquid-phase method (method I) in less time than with the classic chemistry method. The screening of library A revealed that relatively small hydrophobic chains at R1 (5−8 carbons) and small hydrophobic substituents at R2 (1−4 carbons) provided the most potent inhibitors. In accordance with these inhibition results, a second library (B) of 3β-amidomethyl-ADT derivatives (56 members) was generated in a very short time using an improved method based on scavenger resins and liquid-phase parallel chemistry. Library B produced more potent inhibitors than library A and provided useful structure−activity relationships that directed the design of a third library (C) of 49 members. Once again, very potent inhibitors were identified from library C and 3β-[(N-adamantylmethyl-N-butanoyl)aminomethyl]-3α-hydroxy-5α-androstan-17-one (C-7 - 3) was identified as the most potent inhibitor of the three libraries with an inhibitory activity (IC50 = 35 nM) 18-fold higher than that of the natural substrate of the enzyme, Δ4-dione, (IC50 = 650 nM) used itself as inhibitor. Finally, we designed a library (D) of 3-carbamate-ADT derivatives (25 members) using the efficient parallel liquid-phase method III, which allowed the synthesis of more rigid molecules with two levels of molecular diversity (R1/R2 and R3) in the local area occupied by the adamantane group of C-7 - 3. Interestingly, one of the most potent inhibitors of library D, the 3R-spiro-{3‘-[3‘ ‘-N-morpholino-2‘ ‘-(3‘ ‘‘-cyclopentyl-propionyloxy)propyl]-2‘-oxo-oxazolidin-5‘-yl}-5α-androstan-17-one (D-5 - 4), showed an inhibitory activity on type 3 17β-HSD similar to that of compound C-7 - 3, while exhibiting a nonandrogenic profile.