1357564-01-2

Upstream product

• 103291-07-2 4-bromo-1-fluoro-2-methoxy-benzene 
• 31181-90-5 5-bromo-pyridine-2-carbaldehyde 
• 1357563-99-5 (5-bromopyridin-2-yl)-(4-fluoro-3-methoxyphenyl)-methanol 

Downstream Products

• 1357563-43-9 (4-fluoro-3-hydroxyphenyl)-[5-(4-hydroxy-3-methylphenyl)-pyridin-2-yl]-methanone 
• 1357564-03-4 (4-fluoro-3-methoxyphenyl)-[5-(4-methoxy-3-methylphenyl)-pyridin-2-yl]-methanone 
• 1357563-44-0 (4-fluoro-3-hydroxyphenyl)-[5-(3-chloro-4-hydroxyphenyl)-pyridin-2-yl]-methanone 
• 1357564-05-6 (4-fluoro-3-methoxyphenyl)-[5-(3-chloro-4-hydroxyphenyl)-pyridin-2-yl]-methanone 

Relevant academic research and scientific papers

First Structure-Activity Relationship of 17β-Hydroxysteroid Dehydrogenase Type 14 Nonsteroidal Inhibitors and Crystal Structures in Complex with the Enzyme

17β-HSD14 belongs to the SDR family and oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD+ as cofactor. The goal of this study was to identify and optimize 17β-HSD14 nonsteroidal inhibitors as well as to disclose their structure-activity relationship. In a first screen, a library of 17β-HSD1 and 17β-HSD2 inhibitors, selected with respect to scaffold diversity, was tested for 17β-HSD14 inhibition. The most interesting hit was taken as starting point for chemical modification applying a ligand-based approach. The designed compounds were synthesized and tested for 17β-HSD14 inhibitory activity. The two best inhibitors identified in this study have a very high affinity to the enzyme with a Ki equal to 7 nM. The strong affinity of these inhibitors to the enzyme active site could be explained by crystallographic structure analysis, which highlighted the role of an extended H-bonding network in the stabilization process. The selectivity of the most potent compounds with respect to 17β-HSD1 and 17β-HSD2 is also addressed.

Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis

E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyses the conversion between active 17β-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17β-HSD2 inhibitor may provide a new approach in the onset of osteoporosis. Bicyclic substituted hydroxyphenylmethanone derivatives were synthesised as steroidomimetics of the substrate E2 and were evaluated for their 17β-HSD2 inhibition and their selectivity toward 17β-HSD1, catalysing the reverse reaction the conversion of estrone (E1) into E2. Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC50 value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17β-HSD1. These results make compound 12 an interesting candidate for further biological evaluation.