title: In vitro evaluation of the anti-estrogenic activity of hydroxyl substituted diphenylnaphthyl alkene ligands for the estrogen receptor.
abstract: There is still a need for additional scaffolds to further explore tissue selectivity and improving efficacy of selective estrogen receptor modulators (SERMs). A series of hydroxyl substituted diphenylnaphthyl alkene ligands for the two estrogen receptors are described that arose from an initial de novo designed diphenylnaphthyl propylene ligand 1. All compounds gave K(i)s under 10 nM when assayed in the presence of ERalpha. Generally these compounds had very high affinity for both ER isotypes. Moving the hydroxyl group on naphthalene from the 6- to the 5-position of the alpha-naphthalene attached compounds (6b and 6e vs 6c and 6f) had little affect on ER binding nor did altering the position of the naphthalene attachment (alpha or beta) to the alkene moiety. In transfection assays none of the compounds displayed agonistic activity in the absence of E(2). In MCF-7 proliferation assays 6a-d, 6f and 12a-c successfully abrogated E(2) stimulation and resulted in greater than 50% inhibition at 1 microM, a level of efficacy similar to that obtained when the cells were treated with raloxifene. Our results show that this new class of SERMs are good candidates for further study as therapeutic agents for the treatment of breast cancer and osteoporosis.
authors.affiliation: SignalGene Inc., 335 Laird Rd, Unit 2, Guelph, Ontario, Canada N1G 4P7.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schmidt
authors.forename: Gilles B
authors.initials: GB
authors.lastname: Tremblay
authors.forename: Michael A
authors.initials: MA
authors.lastname: Plastina
authors.forename: Fupeng
authors.initials: F
authors.lastname: Ma
authors.forename: Sanjivanjit
authors.initials: S
authors.lastname: Bhal neé Basra
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn-Dufault
authors.forename: Peter R
authors.initials: PR
authors.lastname: Redden
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D045744:Cell Line, Tumor; D020847:Estrogen Receptor Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009281:Naphthalenes / Q000737:chemistry*; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000475:Alkenes; D020847:Estrogen Receptor Modulators; D008024:Ligands; D009281:Naphthalenes; D011960:Receptors, Estrogen