T. I. Richardson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3544–3549
3549
and 3c possess PSA and ClogP values very similar to
the corresponding naphthalene analogs 4b and 4c.
Although these did not stimulate E2 to the same extent
as isopropyl analog 3b, unfortunately, their ED50s in the
immature rat uterine assay were 4–8 times that of the
naphthalenes. As a result, they were dosed higher in
the 10-day E2 assay, and although the trends are similar,
the best benzothiophenes produced E2 levels that were
twice vehicle control. The lower activity of the benzothi-
ophenes in the immature rat uterine assay may be due to
overall lower absorption and/or higher metabolism than
the corresponding naphthalenes (data not available).
therapeutic potential for the treatment of leiomyomas in
premenopausal women.
References and notes
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In conclusion, SAR studies on the 2-aryl positions of the
benzothiophene (3) and the naphthalene (4) ring systems
produced novel SERMs that are potent antagonist in
uterine tissue but cause limited ovarian stimulation, as
judged by increased plasma E2 levels in rats. We identi-
fied a loose correlation between calculated properties
(ClogP and PSA) and measured properties (logBB
and plasma E2). Substituents that confer high PSA
and low ClogP, such as aryl sulfones, produced com-
pounds that caused slight or no increases in serum E2
levels, while the corresponding fluoro analogs with low
PSA and high ClogP increased plasma E2 significantly.
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