Tanaproget

Tanaproget is a novel agonist of progesterone receptor with IC50 of 1.7 nM [1].

Progesterone receptor (PR) is a member of the nuclear receptor superfamily and binding of progesterone causes PR conformational changes, which then changing gene expression. Progesterone plays an important role in female reproduction [1].

In T47D cells, tanaproget caused alkaline phosphatase activity with EC50 value of 0.1 nM. In a mammalian two-hybrid assay, tanaproget showed
50-fold more potent than progesterone. In stromal cells isolated from endometrial, tanaproget (1 nM) significantly suppressed pro-MMP-3 secretion. Also, Tanaproget effectively prevented pro-MMP-3 secretion through IL-1α-mediated stimulation [2].

In endometriosis mice model with human lesions growing on the parietal peritoneum of mice, tanaproget completely regressed human lesions in 58% treated animals. Also, the lesions were smaller and fewer compared with the lesions in placebo-treated mice at the end of therapy [2]. In healthy women, the elimination half-life (t(1/2)) of tanaproget ranged from 12 to 30 h. Tanaproget reduced cervical mucus scores, which suggesting poor production and quality of cervical mucus [3].

References:
[1].  Zhang Z, Olland AM, Zhu Y, et al. Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget. J Biol Chem, 2005, 280(31): 28468-28475.
[2].  Bruner-Tran KL, Zhang Z, Eisenberg E, et al. Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget. J Clin Endocrinol Metab, 2006, 91(4): 1554-1560.
[3].  Bapst JL, Ermer JC, Ferron GM, et al. Pharmacokinetics and safety of tanaproget, a nonsteroidal progesterone receptor agonist, in healthy women. Contraception, 2006, 74(5): 414-418.

Carbon-11 radiolabelling of organosulfur compounds: (11) C synthesis of the progesterone receptor agonist tanaproget.[Pubmed:25965348]

Chemistry. 2015 Jun 15;21(25):9034-8.

Herein a new (11) C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivatives using the novel synthon, (11) CS2 , is reported. This approach has enabled the facile labelling of a potent progesterone receptor (PR) agonist, [(11) C]Tanaproget, by the intramolecular reaction of the acyclic aminohydroxyl precursor with (11) CS2 , which has potential applications as a positron emission tomography radioligand for cancer imaging.

Imaging progesterone receptor in breast tumors: synthesis and receptor binding affinity of fluoroalkyl-substituted analogues of tanaproget.[Pubmed:20355713]

J Med Chem. 2010 Apr 22;53(8):3349-60.

The progesterone receptor (PR) is estrogen regulated, and PR levels in breast tumors can be used to predict the success of endocrine therapies targeting the estrogen receptor (ER). Tanaproget is a nonsteroidal progestin agonist with very high PR binding affinity and excellent in vivo potency. When appropriately radiolabeled, it might be used to image PR-positive breast tumors noninvasively by positron emission tomography (PET). We describe the synthesis and PR binding affinities of a series of fluoroalkyl-substituted 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones, analogues of Tanaproget. Some of these compounds have subnanomolar binding affinities, higher than that of either Tanaproget itself or the high affinity PR ligand R5020. Structure-binding affinity relationships can be rationalized by molecular modeling of ligand complexes with PR, and the enantioselectivity of binding has been predicted. These compounds are being further evaluated as potential diagnostic PET imaging agents for breast cancer, and enantiomerically pure materials of defined stereochemistry are being prepared.

Development of [F-18]fluorine-substituted Tanaproget as a progesterone receptor imaging agent for positron emission tomography.[Pubmed:20496889]

Bioconjug Chem. 2010 Jun 16;21(6):1096-104.

The level of progesterone receptors (PRs) in breast tumors can be used to guide the selection of endocrine therapies for breast cancer patients. To this end, we have prepared a fluorine-18 labeled analogue of Tanaproget, a nonsteroidal progestin with very high PR binding affinity and low affinity for androgen and glucocorticoid receptors, and have studied its tissue distribution in estrogen-primed rats to evaluate its potential for imaging PR levels by positron emission tomography. 4-[(18)F]Fluoropropyl-Tanaproget ([(18)F]9, FPTP) was prepared in three steps, within 140 min at an overall decay-corrected yield of 5% and effective specific activity of >550 Ci/mmol. In biodistribution studies, [(18)F]9 uptake was high in target tissues at both 1 and 3 h (uterus, 4.55 and 5.26%ID/g; ovary, 2.32 and 2.20%ID/g, respectively) and was cleanly blocked by coinjection of excess unlabeled compound. Uterus to blood and muscle activity ratios were 9.2 and 5.2 at 1 h and 32 and 26 at 3 h, respectively. The biodistribution of [(18)F]9 compares favorably to that of previously prepared F-18 labeled steroidal progestins, FENP and FFNP. Its high target tissue uptake efficiency and selectivity, and prolonged retention, suggest that it has excellent promise as a PET imaging agent for PR-positive breast tumors.

Tanaproget (NSP-989) is a novel nonsteroidal progesterone receptor agonist which can bind to the PR from various species with a higher relative affinity than reference steroidal progestins.

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