title: Structural optimization of 2,5-thiophene amides as highly potent and selective 17β-hydroxysteroid dehydrogenase type 2 inhibitors for the treatment of osteoporosis.
abstract: Inhibition of 17β-HSD2 is an attractive mechanism for the treatment of osteoporosis. We report here the optimization of human 17β-HSD2 inhibitors in the 2,5-thiophene amide class by varying the size of the linker (n equals 0 and 2) between the amide moiety and the phenyl group. While none of the phenethylamides (n = 2) were active, most of the anilides (n = 0) turned out to moderately or strongly inhibit 17β-HSD2. The four most active compounds showed an IC₅₀ of around 60 nM and a very good selectivity toward 17β-HSD1, 17β-HSD4, 17β-HSD5, 11β-HSD1, 11β-HSD2 and the estrogen receptors α and β. The investigated compounds inhibited monkey 17β-HSD2 moderately, and one of them showed good inhibitory activity on mouse 17β-HSD2. SAR studies allowed a first characterization of the human 17β-HSD2 active site, which is predicted to be considerably larger than that of 17β-HSD1.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, D-66041 Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Kuiying
authors.initials: K
authors.lastname: Xu
authors.forename: Marie
authors.initials: M
authors.lastname: Wetzel
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Arne
authors.initials: A
authors.lastname: Meyer
authors.forename: Alex
authors.initials: A
authors.lastname: Odermatt
authors.forename: Gabriele
authors.initials: G
authors.lastname: Möller
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002144:Callithrix; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002474:Cell-Free System; D057075:Enzyme Assays; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008958:Models, Molecular; D010024:Osteoporosis / Q000188:drug therapy*; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D050071:Bone Density Conservation Agents; D013876:Thiophenes; D015067:17-Hydroxysteroid Dehydrogenases; C032690:3-alpha-(17-beta)-hydroxysteroid dehydrogenase (NAD(+)); D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human