De novo design, synthesis and evaluation of a non-steroidal diphenylnaphthyl propylene ligand for the estrogen receptor.
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.
Schmidt
Jonathan M
JM
SignalGene Inc., 335 Laird Road, Unit 2, Guelph, Ontario, Canada N1G 4P7.
Mercure
Julie
J
Tremblay
Gilles B
GB
Pagé
Martine
M
Feher
Miklos
M
Dunn-Dufault
Robert
R
Peter
Markus G
MG
Redden
Peter R
PR
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
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