Toripristone

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Toripristone
Toripristone.svg
Clinical data
Other namesRU-40555; 17β-Hydroxy-11β-[4-[methyl(1-methylethyl)amino]phenyl]-17α-(1-propyn-1-yl)estra-4,9-dien-3-one
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C31H39NO2
Molar mass 457.658 g·mol−1
3D model (JSmol)

Toripristone (INN) (developmental code name RU-40555) is a synthetic, steroidal antiglucocorticoid as well as antiprogestogen which was never marketed. [1] [2] It is reported as a potent and highly selective antagonist of the glucocorticoid receptor (GR) (Ki = 2.4 nM), [3] [4] though it also acts as an antagonist of the progesterone receptor (PR). [5] [6] The pharmacological profile of toripristone is said to be very similar to that of mifepristone, except that toripristone does not bind to orosomucoid (α1-acid glycoprotein). [5] The drug has been used to study the hypothalamic-pituitary-adrenal axis and has been used as a radiotracer for the GR. [4] [3] Its INN was given in 1990. [2]

See also

Related Research Articles

Hypothalamus Area of the brain below the thalamus

The hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamus is located below the thalamus and is part of the limbic system. In the terminology of neuroanatomy, it forms the ventral part of the diencephalon. All vertebrate brains contain a hypothalamus. In humans, it is the size of an almond.

Antiandrogen

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

Corticotropin-releasing hormone

Corticotropin-releasing hormone (CRH) is a peptide hormone involved in the stress response. It is a releasing hormone that belongs to corticotropin-releasing factor family. In humans, it is encoded by the CRH gene. Its main function is the stimulation of the pituitary synthesis of ACTH, as part of the HPA Axis.

Hypothalamic–pituitary–adrenal axis Set of physiological feedback interactions

The hypothalamic–pituitary–adrenal axis is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland, and the adrenal glands.

Corticotropes are basophilic cells in the anterior pituitary that produce pro-opiomelanocortin (POMC) which undergoes cleavage to adrenocorticotropin (ACTH), β-lipotropin (β-LPH), and melanocyte-stimulating hormone (MSH). These cells are stimulated by corticotropin releasing hormone (CRH) and make up 15–20% of the cells in the anterior pituitary. The release of ACTH from the corticotropic cells is controlled by CRH, which is formed in the cell bodies of parvocellular neurosecretory cells within the paraventricular nucleus of the hypothalamus and passes to the corticotropes in the anterior pituitary via the hypophyseal portal system. Adrenocorticotropin hormone stimulates the adrenal cortex to release glucocorticoids and plays an important role in the stress response.

17α-Hydroxyprogesterone

17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many other endogenous steroids, including androgens, estrogens, glucocorticoids, and mineralocorticoids, as well as neurosteroids.

Neuroendocrinology is the branch of biology which studies the interaction between the nervous system and the endocrine system; i.e. how the brain regulates the hormonal activity in the body. The nervous and endocrine systems often act together in a process called neuroendocrine integration, to regulate the physiological processes of the human body. Neuroendocrinology arose from the recognition that the brain, especially the hypothalamus, controls secretion of pituitary gland hormones, and has subsequently expanded to investigate numerous interconnections of the endocrine and nervous systems.

Selective progesterone receptor modulator

A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists and full antagonists is that their action differs in different tissues, i.e. agonist in some tissues while antagonist in others. This mixed profile of action leads to stimulation or inhibition in tissue-specific manner, which further raises the possibility of dissociating undesirable adverse effects from the development of synthetic PR-modulator drug candidates.

Hypothalamic–pituitary–gonadal axis

The hypothalamic–pituitary–gonadal axis refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single entity. Because these glands often act in concert, physiologists and endocrinologists find it convenient and descriptive to speak of them as a single system.

11-Deoxycortisol

11-Deoxycortisol, also known as cortodoxone (INN), cortexolone as well as 17α,21-dihydroxyprogesterone or 17α,21-dihydroxypregn-4-ene-3,20-dione, is an endogenous glucocorticoid steroid hormone, and a metabolic intermediate towards cortisol. It was first described by Tadeusz Reichstein in 1938 as Substance S, thus has also been referred to as Reichstein's Substance S or Compound S.

Telapristone

Telapristone (INN), as telapristone acetate, is a synthetic, steroidal selective progesterone receptor modulator (SPRM) related to mifepristone which is under development by Repros Therapeutics for the treatment of breast cancer, endometriosis, and uterine fibroids. It was originally developed by the National Institutes of Health (NIH), and, as of 2017, is in phase II clinical trials for the aforementioned indications. In addition to its activity as an SPRM, the drug also has some antiglucocorticoid activity.

GPER

G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), is a protein that in humans is encoded by the GPER gene. GPER binds to and is activated by the female sex hormone estradiol and is responsible for some of the rapid effects that estradiol has on cells.

Selective glucocorticoid receptor modulator

Selective glucocorticoid receptor modulators (SEGRMs) and selective glucocorticoid receptor agonists (SEGRAs) formerly known as dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of the desirable anti-inflammatory, immunosuppressive, or anticancer properties of classical glucocorticoid drugs but with fewer side effects such as skin atrophy. Although preclinical evidence on SEGRAMs’ anti-inflammatory effects are culminating, currently, the efficacy of these SEGRAMs on cancer are largely unknown.

Demegestone

Demegestone, sold under the brand name Lutionex, is a progestin medication which was previously used to treat luteal insufficiency but is now no longer marketed. It is taken by mouth.

Trimegestone

Trimegestone, sold under the brand names Ondeva and Totelle among others, is a progestin medication which is used in menopausal hormone therapy and in the prevention of postmenopausal osteoporosis. It was also under development for use in birth control pills to prevent pregnancy, but ultimately was not marketed for this purpose. The medication is available alone or in combination with an estrogen. It is taken by mouth.

RU-22930 Chemical compound

RU-22930 is a nonsteroidal antiandrogen (NSAA) related to the NSAAs flutamide and nilutamide (RU-23908) and was developed by Roussel Uclaf but was never marketed. It is a selective antagonist of the androgen receptor and consequently has progonadotropic effects by increasing gonadotropin and testosterone levels via disinhibition of the hypothalamic-pituitary-gonadal axis. Unlike flutamide and nilutamide, the drug is said to be short-acting and inactive by injection, but it has been found to be active topically in animals, and hence could be useful for the treatment of androgen-dependent skin conditions.

Onapristone

Onapristone (INN) is a synthetic and steroidal antiprogestogen with additional antiglucocorticoid activity which was developed by Schering and described in 1984 but was never marketed. It is a silent antagonist of the progesterone receptor (PR), in contrast to the related antiprogestogen mifepristone. Moreover, compared to mifepristone, onapristone has reduced antiglucocorticoid activity, shows little antiandrogenic activity, and has 10- to 30-fold greater potency as an antiprogestogen. The medication was under development for clinical use, for instance in the treatment of breast cancer and as an endometrial contraceptive, but was discontinued during phase III clinical trials in 1995 due to findings that liver function abnormalities developed in a majority patients.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

Pharmacodynamics of spironolactone Mechanisms of action

The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.

References

  1. R.A. Hill; H.L.J. Makin; D.N. Kirk; G.M. Murphy (23 May 1991). Dictionary of Steroids. CRC Press. pp. 101–. ISBN   978-0-412-27060-4.
  2. 1 2 https://mednet-communities.net/inn/db/media/docs/p-innlist61.pdf
  3. 1 2 Steiniger, Bjorn; Kniess, Torsten; Bergmann, Ralf; Pietzsch, Jens; Wuest, Frank (2008). "Radiolabeled Glucocorticoids as Molecular Probes for Imaging Brain Glucocorticoid Receptors by Means of Positron Emission Tomography (PET)". Mini-Reviews in Medicinal Chemistry. 8 (7): 728–739. doi:10.2174/138955708784567403. ISSN   1389-5575. PMID   18537728.
  4. 1 2 Bachmann CG, Linthorst AC, Holsboer F, Reul JM (2003). "Effect of chronic administration of selective glucocorticoid receptor antagonists on the rat hypothalamic-pituitary-adrenocortical axis". Neuropsychopharmacology. 28 (6): 1056–67. doi: 10.1038/sj.npp.1300158 . PMID   12700716.
  5. 1 2 Philibert, D.; Costerousse, G.; Gaillard-Moguilewsky, M.; Nedelec, L.; Nique, F.; Tournemine, C.; Teutsch, G. (1991). "From RU 38486 towards Dissociated Antiglucocorticoid and Antiprogesterone". Antihormones in Health and Disease. Frontiers of Hormone Research. 19. pp. 1–17. doi:10.1159/000419634. ISBN   978-3-8055-5297-4. ISSN   0301-3073.
  6. Fu, Jing; Hu, Lina; Huang, Wei; Zhu, Huili; Wang, Qiushi; He, Fan; Xie, Lingxia; Gan, Xiaoling; Huang, Wei (2012). "Progesterone receptor antagonists and progesterone receptor modulators for endometriosis". In Huang, Wei (ed.). Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD009881.