title: E-ring modified steroids as novel potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
abstract: 17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are an important class of steroidogenic enzymes that regulate the bioavailability of active estrogens and androgens and are as yet a relatively unexploited therapeutic target. Based on our investigations and those of others, E-ring modified steroids were identified as a useful template for the design of inhibitors of 17beta-HSD type 1, an enzyme involved in the conversion of estrone into estradiol. The synthesis and biological evaluation of a new series of N- and C-substituted 1,3,5(10)-estratrien-[17,16-c]-pyrazoles and the corresponding SAR are discussed. Among the N-alkylated analogues, the most potent inhibitor was the 1'-methoxyethyl derivative, 41, with an IC(50) of 530 nM in T47-D human breast cancer cells. The X-ray crystal structure of the 1'-isobutyl derivative, was determined. Further optimization of the template using parallel synthesis resulted in a library of C5'-linked amides from which 73 emerged. This pyridylethyl amide had an IC(50) of 300 nM and its activity, with that of 41, suggests the importance of hydrogen bond acceptor groups in the pyrazole side chain. Both 41 and 73 displayed selectivity over 17beta-HSD type 2, and preliminary investigations showed 41 to be nonestrogenic in vitro in a luciferase reporter gene assay in contrast to the parent pyrazole 25. Molecular modeling studies, which support these findings, and a QSAR, the predictive power of which was demonstrated, are also presented.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down BA2 7AY, U.K.
authors.forename: Delphine S
authors.initials: DS
authors.lastname: Fischer
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Allan
authors.forename: Christian
authors.initials: C
authors.lastname: Bubert
authors.forename: Nigel
authors.initials: N
authors.lastname: Vicker
authors.forename: Andrew
authors.initials: A
authors.lastname: Smith
authors.forename: Helena J
authors.initials: HJ
authors.lastname: Tutill
authors.forename: Atul
authors.initials: A
authors.lastname: Purohit
authors.forename: Lynn
authors.initials: L
authors.lastname: Wood
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D004963:Estrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists; D004967:Estrogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism
chemical_list: D004963:Estrenes; D047628:Estrogen Receptor alpha; D004967:Estrogens; D011720:Pyrazoles; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D008156:Luciferases