title: Novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors with good ADME-related physicochemical parameters.
abstract: Under physiological conditions healthy bones are maintained by a well tightened balance between osteoclast (OCs) and osteoblast (OBs) activity. Disruption of this balance leads to osteoporosis characterized by decline in bone function and skeletal rigidity. Inhibition of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) could help maintaining the appropriate bone mass density by increasing the level of estradiol and testosterone in bone. Herein, we described the synthesis, the physicochemical properties and the biological evaluation of novel N-methylsulfonamide and retro-N-methylsulfonamide derivatives as 17β-HSD2 inhibitors showing high potency (compound 10f, IC₅₀ = 23 nM), with a good selectivity toward 17β-HSD1 (the isoenzyme responsible of the reverse reaction), and a likely good in vitro ADME profile. It was also shown that the acidity of the phenolic hydroxy correlates with the inhibitory potency, suggesting pKa as a predictive parameter for the activity of this class of inhibitors.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Perspicace
authors.forename: Annalaura
authors.initials: A
authors.lastname: Giorgio
authors.forename: Angelo
authors.initials: A
authors.lastname: Carotti
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D002627:Chemistry, Physical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013449:Sulfonamides; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human
keywords: 17β-HSD1; 17β-HSD2; 17β-Hydroxysteroid dehydrogenase type 2; 17β-hydroxysteroid dehydrogenase type 1; 17β-hydroxysteroid dehydrogenase type 2; A-dione; ADME; ADME properties; Aqueous solubility; BDBNXSRLAWWJLY-UHFFFAOYSA-N; BIAIGWIQNONMAW-UHFFFAOYSA-N; BOLMQRQNXIVUII-UHFFFAOYSA-N; CJDUVKSVPAJUGB-UHFFFAOYSA-N; CVLJEOBEVPFRFY-UHFFFAOYSA-N; E2; Enzyme inhibition; FRHNMKNFWOBLST-UHFFFAOYSA-N; FRINQDZEYLJNHP-UHFFFAOYSA-N; FWBCDWYBDIBPOB-UHFFFAOYSA-N; HEWWOXLVHWOXCV-UHFFFAOYSA-N; HGIDCXXUTBGJIY-UHFFFAOYSA-N; HJIPMYQQHXXUJR-UHFFFAOYSA-N; ICFIUYRSPOQXRW-UHFFFAOYSA-N; KIOHYPYDGDIUEP-UHFFFAOYSA-N; KQJBQVYEJBYXHB-UHFFFAOYSA-N; Log P; MBUYCTFZQRXWEF-UHFFFAOYSA-N; MW; N-Methylsulfonamide derivatives; NIURFBGRZZFAIE-UHFFFAOYSA-N; OB; OC; OIOMZDRZILJASQ-UHFFFAOYSA-N; Osteoporosis; PLBSKHREONAECB-UHFFFAOYSA-N; QVMDQMXJSFGISQ-UHFFFAOYSA-N; ROQZUUAYDVZNHP-UHFFFAOYSA-N; RQRVWLDFSXDEPX-UHFFFAOYSA-N; RSBNDQRTKQAMHN-UHFFFAOYSA-N; Retro-N-methylsulfonamide derivatives; SF; Structure–activity relationship; Structure–property relationship; T; XAUKOQDTIZJUFD-UHFFFAOYSA-N; YFYJPTJQMCYDHJ-UHFFFAOYSA-N; absorption, distribution, metabolism and elimination; androstenedione; estradiol; molecular weight; osteoblast; osteoclast; pKa; selectivity factor; tPSA; testosterone; topological polar surface area