Mifepristone, 米非司酮

Progesterone and glucocorticoid receptor antagonist.

A cell-permeable synthetic steroid that acts as a potent selective antagonist of progesterone (PR) and glucocorticoid (GR) receptors in vitro and in vivo. Acts as a silent antagonist at PR and has a higher affinity than progesterone.

Mifepristone is an antagonist of glucocorticoid, progesterone, and androgen receptors (Kis = 0.1, 0.64, and 0.65 nM, respectively). It is selective for these receptors over the mineralocorticoid receptor (MR), estrogen receptor α (ERα), and ERβ (Kis = 640, >200, and >750 nM, respectively). In cell-based assays, mifepristone inhibits alkaline phosphatase activity stimulated by the progesterone receptor agonist R5020 as well as reporter transcription stimulated by either dexamethasone or R5020 (IC50s = 7, 5.9, and 1.3 nM, respectively). It also inhibits synthetic androgen R1881-stimulated reporter transcription in a concentration-dependent manner. Mifepristone (10 µM) inhibits growth of 4-OHT-resistant MCF-7 breast cancer cells in vitro. It also inhibits tumor growth in an SKOV3 ovarian cancer nude mouse xenograft model when administered at doses of 0.5 or 1 mg per day. Formulations containing mifepristone have been used for the induction of medical abortions.

Mifepristone is a derivative of the synthetic progestin norethindrone with antiprogesterone activity. Mifepristone competitively binds to the progesterone receptor, resulting in inhibition of the effects of endogenous or exogenous progesterone. This agent also exhibits antiglucocorticoid and weak antiandrogenic activities.

Mifepristone, also known as RU-486, is a potent synthetic steroidal antiprogesterone which is used as a single dose in combination with misoprostol, a prostaglandin analogue, to induce medical abortion. Mifepristone with misoprostol have not been associated with serum enzyme elevations or with clinically apparent liver injury.

Mifepristone, also known as mifeprex or mifegyne, belongs to the class of organic compounds known as oxosteroids. These are steroid derivatives carrying a C=O group attached to steroid skeleton. Mifepristone is a drug which is used for the medical termination of intrauterine pregnancy through 49 days' pregnancy. also indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and are not candidates for surgery or have had unsuccessful surgery. Mifepristone exists as a solid and is considered to be practically insoluble (in water) and relatively neutral. Mifepristone has been found in human hepatic tissue tissue, and has also been detected in multiple biofluids, such as urine and blood. Within the cell, mifepristone is primarily located in the cytoplasm and membrane (predicted from logP). Mifepristone can be biosynthesized from estrane. Mifepristone is a potentially toxic compound.

Title: Mifepristone

CAS Registry Number: 84371-65-3

CAS Name: (11b,17b)-11-[4-(Dimethylamino)phenyl]-17-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one

Additional Names: 11b-[4-(N,N-dimethylamino)phenyl]-17a-(prop-1-ynyl)-D4,9-estradiene-17b-ol-3-one

Manufacturers' Codes: RU-486; RU-38486

Trademarks: Mifegyne (HMR)

Molecular Formula: C29H35NO2

Molecular Weight: 429.59

Percent Composition: C 81.08%, H 8.21%, N 3.26%, O 7.45%

Literature References: Progesterone receptor antagonist with partial agonist activity. Prepn: J. G. Teutsch et al., EP 57115; eidem, US 4386085 (1982, 1983 both to Roussel-UCLAF). Pharmacology: W. Herrmann et al., C.R. Seances Acad. Sci. Ser. 3 294, 933 (1982). Pituitary and adrenal responses in primates: D. L. Healy et al., J. Clin. Endocrinol. Metab. 57, 863 (1983). Mechanism of action study: M. Rauch et al., Eur. J. Biochem. 148, 213 (1985). Clinical study as abortifacient: B. Couzinet et al., N. Engl. J. Med. 315, 1565 (1986); as postcoital contraceptive: A. Glasier et al., ibid. 327, 1041 (1992). Review of mechanism of action and clinical applications: E. E. Baulieu, Science 245, 1351-1357 (1989). Reviews: I. M. Spitz, C. W. Bardin, N. Engl. J. Med. 329, 404-412 (1993); R. N. Brogden et al., Drugs 45, 384-409 (1993).

Properties: mp 150°. [a]D20 +138.5° (c = 0.5 in chloroform).

Melting point: mp 150°

Optical Rotation: [a]D20 +138.5° (c = 0.5 in chloroform)

Therap-Cat: Abortifacient.

Keywords: Abortifacient/Interceptive.