1396244-67-9

Upstream product

• 3034-55-7 5-bromo-1,3-thiazole 
• 17933-03-8 m-tolylboronic acid 

Downstream Products

• 1396244-72-6 lithium 5-(3-methylphenyl)-1,3-thiazole-2-carboxylate 
• 1396243-52-9 N-(3-methoxyphenyl)-N-methyl-5-(3-methylphenyl)-1,3-thiazole-2-carboxamide 

Relevant academic research and scientific papers

Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17 β-hydroxysteroid dehydrogenase type 2 inhibitors

17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.

Novel, potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors as potential therapeutics for osteoporosis with dual human and mouse activities

17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) is responsible for the oxidation of the highly active estradiol (E2) and testosterone (T) into the less potent estrone (E1) and Δ4-androstene-3,17-dione (Δ4-AD), respectively. As 17β-HSD2 is present in bones and as estradiol and testosterone are able to induce bone formation and repress bone resorption, inhibition of this enzyme could be a new promising approach for the treatment of osteoporosis. Herein, we describe the design, the synthesis and the biological evaluation of 24 new 17β-HSD2 inhibitors in the 5-substituted thiophene-2-carboxamide class. Structure-activity and structure-selectivity relationships have been explored by variation of the sulfur atom position in the central core, exchange of the thiophene by a thiazole, substitution of the amide group with a larger moiety, exchange of the N-methylamide group with bioisosteres like N-methylsulfonamide, N-methylthioamide and ketone, and substitutions at positions 2 and 3 of the thiophene core with alkyl and phenyl groups leading to 2,3,5-trisubstituted thiophene derivatives. The compounds were evaluated on human and mouse enzymes. From this study, a novel highly potent and selective compound in both human and mouse 17β-HSD2 enzymes was identified, compound 21 (IC 50(h17β-HSD2) = 235 nM, selectivity factor toward h17β-HSD1 = 95, IC50 (m17β-HSD2) = 54 nM). This new compound 21 could be used for an in vivo proof of principle to demonstrate the true therapeutic efficacy of 17β-HSD2 inhibitors in osteoporosis. New structural insights into the active sites of the human and mouse enzymes were gained.

BIARYL DERIVATIVES AS SELECTIVE 17BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 2 INHIBITORS

The invention relates to selective, non-steroidal 17beta-hydroxysteroid dehydrogenase type 2 (17beta-HSD2) inhibitors of formula (I), their production and use, notably for the treatment and prophylaxis of sex steroid deficient diseases like osteoporosis in men and women.