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The SARfaris: GPCR, Kinase, ADME

Tuesday, 17 August 2010

2010 New Drug Approval - Pt. X - Ulipristal Acetate (Ella)

ATC code: G03AD02

The most recent approval by FDA is Ulipristal Acetate, approved on August 13th 2010 under the trade name Ella. Ulipristal Acetate (previously known by the research code CDB-2914 or VA-2914) is a progesterone agonist/antagonist emergency contraceptive, indicated for prevention of pregnancy following unprotected intercourse or known or suspected contraceptive failure.
This drug is a selective progesterone receptor modulator (SPRM) with antagonist and partial agonist effects (a progesterone agonist/antagonist) at the progesterone receptor (PR, NR3C3) (Uniprot code: P06401). The Progesterone Receptor is a member of a very significant family of proteins for drug discovery, the Nuclear Receptors, a family of around 50 genes which are transcription factors, the transcription by NRs is usually ligand regulated. Ulipristal Acetate prevents progesterone, the endogenous ligand, from occupying its receptor. Ulpristal Acetate binds in the ligand binding domain (LBD) of PR (PFAM: PF00104).

There are several structures known of PR complexed with ligands, a representative one is (PDB: 3D90). Ulipristal Acetate will compete with Levonorgestrel, another progestagen available on the market, which is approved for use up to three days post-intercourse as opposed to five days in the case of Ulipristal Acetate.
Ulipristal Acetate is a small-molecule, natural product derived drug (Molecular Weight 475.6 g.mol-1), Rule-of-Five compliant and it is delivered as a tablet. Ulispristal Acetate is highly bound to plasma proteins (>94%), including high density lipoprotein, alpha-1-acid glycoprotein, and albumin. It is metabolized to mono- and di-demethylated metabolites, mostly by CYP3A4; the mono-demethylated metabolite pharmacologically active. Ulpristal Acetate shows high affinity for the related nuclear receptor - glucocorticoid receptor (GR, NR3C1). The terminal half-life of Ulipristal Acetate is ca. 32 hours. The recommended dosage is one tablet (30 mg) taken orally, with or without food, as soon as possible, within 120 hours (five days) after unprotected intercourse or a known or suspected contraceptive failure.
The full prescribing information can be found here.
The structure 17alpha-acetoxy-11beta-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione is a synthetic progestagen and is thus very similar to progesterone. Like other steroid hormones of this class, Ulipristal Acetate is characterized by its basic 21-carbon skeleton, i.e., four interconnected cyclic hydrocarbons with two methyl branches and a ketone. In this particular case, one of the methyl groups is replaced by a substituted aromatic amine.
NAME="Ulipristal Acetate"
ATC_code= NA
The license holder is Laboratoire HRA Pharma.

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