The preclinical biology of a new potent and selective progestin: trimegestone.
Trimegestone (TMG) is a 19-norpregnane progestin being developed, in combination with an estrogen, for the treatment of postmenopausal symptoms. TMG binds to the human progesterone receptor with an affinity greater than medroxyprogesterone acetate (MPA), norethindrone (NET), and levonorgestrel (LNG). In contrast, TMG binds with low affinity to the androgen, glucocorticoid and mineralocorticoid receptor and has no measurable affinity for the estrogen receptor. Compared to other progestins, TMG demonstrates an improved separation of its PR affinity from its affinity to other classical steroid hormone receptors. In vivo, TMG has potent progestin activity. For example, TMG produces glandular differentiation of the uterine endometrium in rabbits and is about 30 and 60 times more potent than MPA and NET, respectively. In the rat, TMG maintains pregnancy, induces deciduoma formation, inhibits ovulation and has uterine anti-estrogenic activity. With respect to these endpoints, TMG appears to be more potent and selective on uterine epithelial responses than other classical progestin responses. In vivo, TMG does not have significant androgenic, glucocorticoid, anti-glucocorticoid or mineralocorticoid activity but does have anti-mineralocorticoid activity and modest anti-androgenic effects. This overall profile is qualitatively similar to progesterone. When TMG is administered chronically, it antagonizes the effect of estradiol on the uterus but does not antagonize the beneficial bone sparing activity of estradiol. In rat studies evaluating CNS GABAA receptor modulatory activity, TMG is less active on this likely undesirable endpoint than progesterone and norethindrone acetate, which may translate into fewer mood-related side effects. The results indicate that TMG is a potent and selective progestin with a preclinical profile well suited for hormone replacement therapy.
Winneker
Richard C
RC
Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. winnekr@wyeth.com
Bitran
Daniel
D
Zhang
Zhiming
Z
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive; D001842:Bone and Bones / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011372:Progestins / Q000737:chemistry*; D011397:Promegestone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D011987:Receptors, Steroid / Q000737:chemistry; D013997:Time Factors
D011372:Progestins; D011987:Receptors, Steroid; C050319:trimegestone; D011397:Promegestone