title: De novo design, synthesis and evaluation of a non-steroidal diphenylnaphthyl propylene ligand for the estrogen receptor.
abstract: There is still a strong need for additional diversity and new chemical scaffolds to allow for the exploration of improved tissue selectivity and finding better selective estrogen receptor modulators (SERMs). Using a de novo design technology a diphenylnaphthyl propylene scaffold, exemplified by (E)-9b, with ER antagonist activity has been generated. It was prepared by alkylating 1-[4-methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl]-1-propanone under metal halogen exchange conditions with 1-iodo-6-methoxy-naphthalene. Following dehydration and cleavage of the methoxy groups, (E)-9b was formed by displacement of the chloro group with pyrrolidine. (E)-9b binding to ER generated calculated K(i) values of 3.7 nM for hER(alpha) and 72 nM for hER(beta). The antagonism of (E)-9b was demonstrated in cell transfection assays using the ERE from the vitA2 promotor and the natural ER-responsive pS2 promotor. With increasing concentrations of (E)-9b, the E(2)-dependent response was efficiently inhibited demonstrating that (E)-9b could function as an anti-estrogen in these assays. Interestingly, ER(alpha) activity was inhibited even below basal levels suggesting that ligand-independent activity of ER(alpha) was also inhibited. Computational docking studies suggest that the placement of the hydroxyl group on the naphthalene group may not be optimal and we are currently exploring additional analogues.
authors.affiliation: SignalGene Inc., 335 Laird Road, Unit 2, Guelph, Ontario, Canada N1G 4P7.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Schmidt
authors.forename: Julie
authors.initials: J
authors.lastname: Mercure
authors.forename: Gilles B
authors.initials: GB
authors.lastname: Tremblay
authors.forename: Martine
authors.initials: M
authors.lastname: Pagé
authors.forename: Miklos
authors.initials: M
authors.lastname: Feher
authors.forename: Robert
authors.initials: R
authors.lastname: Dunn-Dufault
authors.forename: Markus G
authors.initials: MG
authors.lastname: Peter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Redden
mesh_terms: D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D015195:Drug Design; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D011407:Propane / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride / Q000737:chemistry; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*; D014162:Transfection
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D009281:Naphthalenes; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C478570:diphenylnaphthyl propylene; D020849:Raloxifene Hydrochloride; D008156:Luciferases; D011407:Propane