title: Synthesis and pharmacology of conformationally restricted raloxifene analogues: highly potent selective estrogen receptor modulators.
abstract: The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. In vivo structure-activity relationships and molecular modeling studies have indicated that the orientation of the basic amine-containing side chain of 1, relative to the stilbene plane, is an important discriminating factor for the maintenance of tissue selectivity. We have constructed a series of analogues of 1 in which this side chain is held in an orientation which is orthogonal to the stilbene plane, similar to the low-energy conformation predicted for raloxifene. Herein, we report on the synthesis of these compounds and on their activity in a series of in vitro and in vivo biological assays reflective of the SERM profile. In particular, we describe their ability to (1) bind the estrogen receptor, (2) antagonize estrogen-stimulated proliferation of MCF-7 cells in vitro, (3) stimulate TGF-beta3 gene expression in cell culture, (4) inhibit the uterine effects of ethynyl estradiol in immature rats, and (5) potently reduce serum cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like stimulation of uterine tissue. These data demonstrate that one of these compounds, LY357489,4, is among the most potent SERMs described to date with in vivo efficacy on bone and cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Grese
authors.forename: L D
authors.initials: LD
authors.lastname: Pennington
authors.forename: J P
authors.initials: JP
authors.lastname: Sluka
authors.forename: M D
authors.initials: MD
authors.lastname: Adrian
authors.forename: H W
authors.initials: HW
authors.lastname: Cole
authors.forename: T R
authors.initials: TR
authors.lastname: Fuson
authors.forename: D E
authors.initials: DE
authors.lastname: Magee
authors.forename: D L
authors.initials: DL
authors.lastname: Phillips
authors.forename: E R
authors.initials: ER
authors.lastname: Rowley
authors.forename: P K
authors.initials: PK
authors.lastname: Shetler
authors.forename: L L
authors.initials: LL
authors.lastname: Short
authors.forename: M
authors.initials: M
authors.lastname: Venugopalan
authors.forename: N N
authors.initials: NN
authors.lastname: Yang
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: A L
authors.initials: AL
authors.lastname: Glasebrook
authors.forename: H U
authors.initials: HU
authors.lastname: Bryant
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D020849:Raloxifene Hydrochloride; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
chemical_list: D004965:Estrogen Antagonists; C111644:LY 357489; D009285:Naphthoquinones; D010880:Piperidines; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D020849:Raloxifene Hydrochloride; D002784:Cholesterol