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The SARfaris: GPCR, Kinase, ADME

Sunday, 2 January 2011

New Drug Approvals 2010 - Pt. XIX Dienogest (NataziaTM)

ATC code: G03AB08 and G03FA15 (as combinations)

On May 6th 2010, the FDA approved Dienogest, as a component of the oral contraceptive drug Natazia (tradename:Natazia, tradename:Qlaira). Dienogest (research code:STS-557) is a progestin is a synthetic analog of the natural product progesterone. Dienogest is one of two active components within Natazia, the other being the 17ß-estradiol prodrug - estrogen valerate; Natazia is therefore a Combination Oral Contraceptive (or COC). Natazia is the first four-phase combined oral contraceptive marketed in the United States - the four phases refering to the differential dosing of the estrogen/progestin throughout the menstrual cycle. Each monthly pack of Natazia contains pills to be taken in a specific order: 2 dark yellow tablets each containing 3 mg estradiol valerate; then 5 medium red tablets each containing 2 mg estradiol valerate and 2 mg dienogest; then 17 light yellow tablets each containing 2 mg estradiol valerate and 3 mg dienogest; then 2 dark red tablets each containing 1 mg estradiol valerate; and finally 2 white tablets (inert/placebo).

The -gest- INN stem covers progestins, a large pharmacological class of steroid structures, including (alongside dienogest) - demegestone, desogestrel, dydrogesterone, etonogestrel, gestodene, gestonorone, gestrinone, hydroxyprogesterone, levonorgestrel, medrogestone, medroxyprogesterone,
megestrol, nomegestrol, norelgestromin, norgestimate, norgestrel, norgestrienone, progesterone, promegestone, quingestanol, and trimegestone. These are usually in the G03 ATC class (Sex hormones and modulators of the genital system) and are often dosed as combination with other steroid hormones (estrogens and/or androgens). Some members of this set are in the L02 ATC class (Endocrine therapy, Antineoplastic and immunomodulatory agents)

Dienogest is a synthetic derivative of the natural steroid progesterone, and acts via similar targets to the endogenous steroid - primarily through binding to the Progesterone Receptor (PR), specifically dienogest acts as a PR agonist, with an EC50 of 3.1 nM for human PR. Progesterone Receptor (Uniprot:P06401, ChEMBL:CHEMBL208, synonym:PGR, synonym:NR3C3) is a homodimeric nuclear hormone receptor (NHR) with the drug binding at a well defined site within the ligand-binding domain (Pfam:PF00104). The nuclear receptor family are a very significant family of drug targets, with the most pharmacologically relevant members of the family acting as ligand-regulated transcription factors. Dienogest is a 19-nortestosterone derivative, and displays some androgen-related pharmacology (in the case of dienogest, it acts as an anti-androgen, with an EC50 of 420 nM). Dienogest shows no significant glucococorticoid (GR) or mineralocorticoid (MR) activity.

There is a wealth of structural data available for the molecular target of dienogest - PR, an example structure is PDBE:3d90 which is in complex with the related progestin levonorgestrol. The ligand-binding domain structure of many nuclear receptors is known, and the ligand typically fills a central hydrophobic cavity, altering the surface topology around this ligand-dependent surface site, that then can bind various co-activators/co-repressors. There are a large set of potential co-activators/co-repressors, often expressed in a tissue-specific manner. This aspect offers the potential to pharmacologically differentiate ligands directed against NHRs - leading to the identification of clinical stage PR antagonists (USAN stem -pristone, e.g. mifepristone), selective progesterone receptor modulators (SPRMs) (USAN stem -prisnil, e.g. asoprisnil), as well as agonists that are non-steroidal agonists of PR (USAN stem -proget, e.g. tanaproget).

Dienogest (IUPAC:(17α)-17-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile, INCHIKEY:AZFLJNIPTRTECV-FUMNGEBKSA-N, SMILES:CC12CCC3=C4CCC(=O)C=C4CCC3C1CCC2(CC#N)O , PubChem:CID68861, Chemspider:62093); has a molecular weight of 311.42 Da, has one hydrogen bond donor, three hydrogen bond acceptors, a calculated logP of 1.8, and a topological surface area of 61.1 Å2. It is therefore completely compliant with Lipinski's rule of five. There are no ionisable centers (over a biologically relevant pH range) and therefore dienogest is neutral under physiological coniditions. The four rings of the classic steroid core are obvious in the structure, and all chiral centers are present with a defined stereochemistry. Dienogest, like all steroids, is also a very rigid molecule, with only one free rotatable bond. A feature of note in the structure is the presence of the nitrile group, in which the carbon atom is reasonably electrophilic (and therefore accessible to attack by nucleophiles) -  some drugs, e.g. saxagliptin use a nitrile as a reactive group for covalent binding to the target. However, in dienogest, the nitrile does not have a mechanistic role in target modulation. Dienogest was first synthesized in the late 1970s.

Dienogest is highly bioavailable (91%) when orally dosed, and has a half-life of 12.3 hr. Following i.v. dosing, dienogest has a volume of distribution (Vd) of 46 L, and a total Clearence of 5.1 10% of circulating dienogest is in a free form, while 90% is bound to serum albumin. In contrast to many steroid like drugs, no significant binding to the steroid carrier proteins - sex-hormone binding globulin (SHBG) and corticosteroid-binding globulin (CBG) is reported. Dienogest is extensively metabolised and cleared by CYP3A4 and other pathways responsible for endogenous steroid catabolism (leading to hydroxylation and conjugation), clearance is primarily in the form of metabolites via the renal route. This reliance on CYP3A4 for metabolism leads to multiple opportunities for drug-drug interactions with both CYP3A4 inhibitors and inducers. At the 3mg dose level used in Natazia, the daily molar dose is 9.6 µmol. The average steady-state plasma concentration (for a p.o. dose of 3 mg o.d.) of dienogest is 33.7 ng/ml (equivalent to 0.11 µM)

Dienogest has a black box warning - and should not be used in smokers over 35 - in this population the risk of cardiovascular events is increased.

The full US prescribing information (for Natazia) can be found here. The same product as Natazia, but branded as Qlaira has been available within parts of Europe since 2008 - the Summary of Product Characteristics (SPC) for Qlaira is here. An earlier product (Climodien) containing dienogest, but indicated for hormone replacement therapy (HRT), has been available within some parts of the EU since 2001. The SPC for Climodien is available here.

The license holder is Bayer Healthcare and the product website is

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