Ulipristal Acetate

Description

Ulipristal acetate is a synthetic steroid derived from 19-nor-progesterone that exerts potent progesterone receptor (PR) antagonist activity at the transcriptional level. It is an orally administered drug indicated for emergency contraception (i.e., postcoital contraception) up to 120 h following unprotected intercourse. Ulipristal acetate is the second oral progestogen marketed for this indication behind levonorgestrel. As PR antagonists, both drugs are believed to act via delay of ovulation and inhibition of follicular development. Levonorgestrel 1.5 mg is approved for contraception up to 72 h following unprotected intercourse and is widely accessible via prescription, and directly from clinics and community pharmacies. Prior to ulipristal acetate, the only approved postcoital contraceptive option between 72 and 120 h was the insertion of an intrauterine device (IUD). The recommended dose of ulipristal acetate is one 30-mg tablet taken as soon as possible and no more than 120 h following intercourse. The vast majority of PR antagonists belonging to the mifepristone (RU486) family also bind to the glucocorticoid receptor (GR) with high affinity and thereby exert antiglucocorticoid activity.
The most common adverse effects with ulipristal acetate were headache, dysmenorrhea, nausea, abdominal pain, dizziness, fatigue, and upper abdominal pain.

Chemical properties

Pale Yellow Solid

Originator

Research Triangle Institute (US)

The Uses of Ulipristal Acetate

Ulipristal acetate is a selective progesterone receptor modulator

The Uses of Ulipristal Acetate

Α selective labelled progesterone receptor modulator

The Uses of Ulipristal Acetate

Labelled Ulipristal

Definition

ChEBI: A 20-oxo steroid obtained by acetylation of the 17-hydroxy group of (11beta,17alpha)-17-acetyl-11-[4-(dimethylamino)phenyl]-3-oxoestra-4,9-dien-17-ol (ulipristal). A selective progesterone receptor modulator, which is empl yed as an emergency contraceptive.

brand name

ellaOne

Biochem/physiol Actions

Ulipristal acetate is a selective progesterone receptor modulator (SPRM) with tissue-selective partial antagonist activity. It has clinical use both as an emergency contraceptive and as a treatment for uterine fibroids. Ulipristal acetate acts as a partial antagonist on the hypothalamic–pituitary–ovarian axis to inhibit or delay ovulation without affecting human embryo implantation. As a progesterone antagonist, Ulipristal acetate selectively suppresses neo-vascularization, cell proliferation, and survival in uterine fibroid cells, but not in normal myometrial cells.

Clinical Use

Ulipristal acetate, a selective progesterone receptor modulator (SPRM), was developed at the Research Triangle Institute. In 2009, HRA Pharma received FDA approval for emergency contraception within 120 h (5 days) of unprotected sexual intercourse or contraceptive failure. Ulipristal acetate is a well-known steroid that possesses antiprogestational and antiglucocorticoid activity. It is the first SPRM that was specifically designed as an oral emergency contraceptive. Unlike earlier levonorgestrel-based emergency contraceptives, this SPRM drug maintains efficacy for 5 days after unprotected intercourse while having safety profile comparable to levonorgestrel.

Synthesis

Recently, an industrial scale route was published and is described in the scheme.89 Alkylation of commercially available 3-(ethylenedioxy)-19-estra-5(10),9(11)- diene-17-one (129, multiple vendors) with tBuOK and acetylene in THF at 0??C gave alcohol 130 in 95% yield, which was subsequently treated with phenylsulfenyl chloride in the presence of TEA and AcOH in DCM/CHCl3 at 5??C to 0??C to effect thiolester formation followed by sulphinate-sulphoxide rearrangement to give allene sulphoxide 131 in 88% yield. Compound 131 was treated with NaOMe/MeOH at 64??C to give the corresponding enol ether and then the enol ether was treated with trimethyl phosphite at the same temperature for sulphoxide-sulphinate rearrangement to furnish hydroxyl enol ether 132 in 67% yield. Compound 132 was demethylated with 1 M HCl in methanol to give the corresponding ketone 133 in 95% yield which was protected using ethylene glycol, pTsOH and trimethyl orthophosphate in DCM to afford cyclopentyl ketal 134 in 87% yield. Epoxidation of 134 in the presence of hexachloroacetone and H2O2 in pyridine and DCM at 0??C provided a 55:45 mixture of the 5-a,10-a epoxides (135, 136). The crude epoxides 135 and 136 were reacted with 4-( N,N-dimethylamino)-phenyl magnesium bromide in THF in the presence of CuCl in DCM to furnish the mixture of diastereomers 137 and 138 in 46% yield over two steps. The mixture (137 and 138) was then treated with KHSO4 in water at 5??C to affect dehydration and liberation of the keto functional group to give 139 which was used in the next step without isolation. Compound 139 was acetylated with acetic anhydride and perchloric acid in DCM at 30??C to afford the ulipristal acetate (XXI) in 66% yield over the final two steps.