title: Novel, potent inhibitors of 17beta-hydroxysteroid dehydrogenase type 1.
abstract: Many breast tumours are hormone-responsive and rely on estrogens for their sustained growth and development. The enzyme 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) is primarily responsible for the conversion of estrone (E1) into the most potent of the human estrogens 17beta-estradiol (E2). Here we report the syntheses, inhibitory activities and docking studies for a novel series of pyrazole amides which have been discovered with the aim of probing the structure activity relationships (SAR) for such a template and of using this template to mimic the potent inhibitor 1 (Fig. 1). Amides containing an aromatic pyridyl moiety have been found to give the best inhibition, indicating that the pyridyl group interacts beneficially in the active site. This work has shown that extension from this position on the pyrazole template is well tolerated and the optimization of such systems is under investigation.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology and Sterix Ltd., University of Bath, Claverton Down BA2 7AY, UK.
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: Michael J
authors.initials: MJ
authors.lastname: Reed
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D004970:Estrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C510578:2-ethyl-16-((3-pyridylmethylamino)carbonylmethyl)estrone; D000577:Amides; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D004970:Estrone; D004960:Estradiol Dehydrogenases