Women's Health Research Institute, Wyeth-Ayerst Research, Collegeville, Pennsylvania 19426, USA
Address for correspondence: Dr. Barry S. Komm, Women's Health Research Institute, Wyeth-Ayerst Research, Collegeville, PA 19426. Voice: 484-865-2776; fax: 484-865-9368.
kommb{at}war.wyeth.com
Estrogens are represented by a diverse group of compounds. Within
this large family of molecules are tissue-selective estrogens
that have been classified as selective estrogen receptor modulators
(SERMs). These compounds are characterized by the fact that
they exhibit both estrogen agonist and antagonist activity dependent
upon the gene promoter and target tissue being examined. SERMs
have been intensively studied over the past decade, especially
since one, raloxifene, has been approved for the prevention
and treatment of postmenopausal osteoporosis. While not a replacement
for hormone replacement therapy (HRT), raloxifene can be an
alternative to it and other treatments for osteoporosis. The
ideal SERM would provide the positive benefits associated with
HRT without the uterine and breast stimulation. Raloxifene does
achieve some of the benefits of HRT, specifically on the skeleton
and lipid metabolism with no apparent uterine effects, and a
potential decreased risk of developing breast cancer associated
with raloxifene therapy. However, there are a number of parameters
that can be improved. A number of SERMs have been evaluated
only to fail in development due to, for the most part, uterine
safety issues. In order to develop an improved SERM, a stringent
screening process was designed to select compounds that did
not stimulate the uterus or breast. At the same time, these
new compounds would have a positive impact on the skeleton and
lipid metabolism with the additional improvement (over raloxifene)
of a neutral effect on hot flashes. Under these strict conditions,
WAY-140424 was developed and, to date, the preclinical pharmacology
data have accurately predicted the clinical response demonstrated
in phase I and II trials.
