Development of the selective progesterone receptor modulator CDB-2914 for clinical indications.
CDB-2914 (17 alpha-acetoxy-11 beta-[4-N,N-dimethylaminophenyl]-19-norpregna-4,9-diene-3,20-dione) is a 19-norprogesterone derivative that acts as an antagonist in progesterone-responsive tissues. It binds to progesterone receptors A and B with high affinity. After oral dosing in humans, CDB-2914 serum levels peak at 60-90 min. CDB-2914 binds to serum proteins and is cleared slowly. Doses of 1, 10 and 50 mg exhibit proportional increases in peak serum levels, but serum levels from higher doses, 100 and 200 mg, are not dose-dependent, suggesting saturation of carrier sites. The biological effects of CDB-2914 vary according to time of the menstrual cycle that the drug is given. In the mid-follicular phase, CDB-2914 (50 mg) inhibits follicular development and delays ovulation and menses. At 100 mg, in some cases the original follicle ceases development and a new follicle is recruited. Endometrial maturation is delayed at all doses tested (10, 50, 100 mg). Given at mid-luteal phase, there was a dose-dependent effect on menses, with higher doses (100-200 mg) resulting in earlier menses. On average, CDB-2914 tends to lengthen the menstrual cycle by approximately 1-2 days although the amount of delay varies with timing in the menstrual cycle and dose.
Blithe
Diana L
DL
Department of Health and Human Services, National Institute of Child Health and Human Development, National Institutes of Health Building 61E, Room 8B13, Bethesda, MD 20892, USA. blithed@nih.gov
Nieman
Lynnette K
LK
Blye
Richard P
RP
Stratton
Pamela
P
Passaro
Maureen
M
D003270:Contraceptive Agents / Q000737:chemistry / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects; D005260:Female; D006801:Humans; D008597:Menstrual Cycle / Q000187:drug effects; D009649:Norpregnadienes / Q000737:chemistry / Q000493:pharmacokinetics*; D010053:Ovary / Q000187:drug effects; D010060:Ovulation / Q000187:drug effects; D010919:Placebos; D011374:Progesterone / Q000378:metabolism; D013997:Time Factors
D003270:Contraceptive Agents; D009649:Norpregnadienes; D010919:Placebos; D011374:Progesterone; C094854:ulipristal