title: Novel, potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors as potential therapeutics for osteoporosis with dual human and mouse activities.
abstract: 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 Δ(4)-androstene-3,17-dione (Δ(4)-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 (IC50(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.
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors: Enrico
authors: E
authors: Perspicace
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany; Dipartimento Farmaco-Chimico, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
authors: Liliana
authors: L
authors: Cozzoli
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany.
authors: Emanuele M
authors: EM
authors: Gargano
authors: ElexoPharm GmbH, Campus A1(2), D-66123 Saarbrücken, Germany.
authors: Nina
authors: N
authors: Hanke
authors: Dipartimento Farmaco-Chimico, Università degli Studi di Bari, V. Orabona 4, I-70125 Bari, Italy.
authors: Angelo
authors: A
authors: Carotti
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany; Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: rolf.hartmann@helmholtz-hzi.de.
authors: Rolf W
authors: RW
authors: Hartmann
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2(3), D-66123 Saarbrücken, Germany. Electronic address: s.marchais@mx.uni-saarland.de.
authors: Sandrine
authors: S
authors: Marchais-Oberwinkler
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010024:Osteoporosis / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000737:chemistry; D013854:Thioamides / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007659:Ketones; D013449:Sulfonamides; D013854:Thioamides; D013876:Thiophenes; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: 17β-hydroxysteroid dehydrogenase type 2; Estrogen receptor; Inhibitor; Osteoporosis; Structure–activity relationships