Estrogen receptor ligands. Part 7: Dihydrobenzoxathiin SERAMs with bicyclic amine side chains

Bioorganic and Medicinal Chemistry Letters

Volumn 14, Issue 15, 2004, Pages 3861-3864

  Blizzard, Timothy A ^a   DiNinno, Frank ^a   Morgan II, Jerry D ^a   Chen, Helen Y ^a   Wu, Jane Y ^a   Gude, Candido ^a   Kim, Seongkon ^a   Chan, Wanda ^a   Birzin, Elizabeth T ^a   Yang, Yi Tien ^a   Pai, Lee Yuh ^a   Zhang, Zhoupeng ^a   Hayes, Edward C ^a   DaSilva, Carolyn A ^a   Tang, Wei ^a   Rohrer, Susan P ^a   Schaeffer, James M ^a   Hammond, Milton L ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Estrogen; SERAMs; SERMs

Indexed keywords

AMINE; ESTROGEN RECEPTOR ALPHA; SELECTIVE ESTROGEN RECEPTOR ALPHA MODULATOR; SELECTIVE ESTROGEN RECEPTOR MODULATOR; UNCLASSIFIED DRUG;

ARTICLE; CHEMICAL MODIFICATION; DRUG ACTIVITY; DRUG SYNTHESIS; STRUCTURE ANALYSIS; UTERUS;

ANIMALS; BICYCLO COMPOUNDS; FEMALE; KINETICS; LIGANDS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; RECEPTORS, ESTROGEN; SELECTIVE ESTROGEN RECEPTOR MODULATORS; STRUCTURE-ACTIVITY RELATIONSHIP; UTERUS;

EID: 3042642772     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2004.05.074     Document Type: Article

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29. Analytical chiral HPLC performed on a Chiralcel OD 4.6 mm × 250 mm 10 μm column eluted with 60:40 heptane-isopropanol at 0.5 mL/min. Retention times: ( - )enantiomer of 30 (converts to 8a) 16 min; ( + )enantiomer (converts to 9a) 20 min
30. The absolute stereochemistry of diasteromers 8 and 9 (and thus enantiomers 8a and 9a) was assigned by analogy with compounds of known stereochemistry based on uterine assay data. These related compounds will be disclosed in a future publication
31. 50 values that are reproducible to within a factor of 2-3. Benzoxathiin 1 (n=36) and estradiol (n>100) were tested in multiple assays; data reported in Table 1 is an average of all determinations
32. 50 determined
33. The cyanide adduct assay was used as a surrogate measure of protein adduct formation subsequent to microsomal oxidation. Compounds were incubated with liver microsomes in the presence of cyanide ion then LC-MS was used to analyze for the presence of cyanide adducts
34. (a) The uterine weight assay is an in vivo assay that measures estrogen agonism and antagonism in rat uterine tissue. Compounds are dosed orally at 1 mpk. Agonism reported as % of estradiol control; antagonism reported as % antagonism of estradiol
35. (b) Estradiol exhibited 100% agonism @ 4 μg/kg