launched 2000 by Mitsubishi Tanabe Pharma
Taltirelin tetrahydrate, Taltirelin hydrate, 201677-75-0, TA 0910
Molecular Formula: C17H31N7O9 Molecular Weight: 477.46954
Taltirelin (marketed under the tradename Ceredist) is a thyrotropin-releasing hormone (TRH) analog, which mimics the physiological actions of TRH, but with a much longer half-life and duration of effects, and little development of tolerance following prolonged dosing. It has nootropic, neuroprotective and analgesic effects.
Taltirelin is primarily being researched for the treatment of spinocerebellar ataxia; limited research has also been carried out with regard to other neurodegenerative disorders, e.g., spinal muscular atrophy.
Taltirelin is a thyrotropin-releasing hormone (TRH) analog that was first commercialized by Tanabe Seiyaku (now Mitsubishi Tanabe Pharma) in Japan in 2000 for the oral treatment of ataxia due to spinocerebellar degeneration.
In 2008, the company filed a regulatory application seeking approval of taltirelin orally disintegrating tablets for the treatment of spinocerebellar degeneration, and in 2009 the approval was received for this formulation.
TRH is a tripeptide hormone that stimulates the release of thyroid-stimulating hormone and prolactin by the anterior pituitary. TRH is produced by the hypothalamus and travels across the median eminence to the pituitary via the hypophyseal portal system.
Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R
Synthesis and central nervous system actions of thyrotropin-releasing hormone analogues containing a dihydroorotic acid moiety
J Med Chem 1990, 33(8): 2130\
(1) 1.56 g of 1-methyl-L-4,5-dihydroorotic acid and 1.15 g of N-hydroxysuccinimide are dissolved in 30 ml of dimethylformamide, and 2.06 g of dicyclohexylcarbodiimide are added thereto at 0° C. The mixture is stirred at room temperature for 2 hours. The solution thus obtained is hereinafter referred to as “Solution A”. On the other hand, 3.43 g of benzyl L-histidyl-L-prolinate.2HCl are dissolved in dimethylformamide, and 1.67 g of triethylamine are added thereto. The mixture is stirred at 0° C. for 20 minutes, and insoluble materials are filtered off. The filtrate is added to “Solution A”, and the mixture is stirred at 0° C. for 4 hours and then at 10° C. for one day. Insoluble materials are filtered off, and the filtrate is concentrated under reduced pressure at 40° C. to remove dimethylformamide. The residue is dissolved in water, and insoluble materials are filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. The column is washed with 500 ml of water, 500 ml of 20% methanol and 300 ml of 50% methanol, successively. Then, the desired product is eluted with 70% methanol. The fractions which are positive to the Pauly’s reaction are collected from the eluate and concentrated under reduced pressure, whereby 3.65 g of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are obtained as an oil.
IRνmax chloroform (cm-1) 3300, 1725, 1680.
650 mg of the product obtained above are dissolved in 1 N-HCl and then lyophilized to give 690 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate.HCl.H2 O as powder.
[α]D 22 : -39.8° (C=0.5, H2 O).
IRνmax nujol (cm-1): 1720, 1640-1680.
NMR (DMSO-d6, δ): 1.7-2.4 (m, 4H), 2.90 (s, 3H), 2.4-3.9 (m, 6H), 3.9-4.2 (m, 1H), 4.3-4.5 (m, 1H), 4.6-5.0 (m, 1H), 5.09 (s, 2H), 7.2-7.5 (m, 5H), 8.96 (s, 1H).
Mass (m/e): 496 (M+).
(2) 700 mg of benzyl (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinate are dissolved in 20 ml of methanol, and 20 mg of palladium-black are added thereto. The mixture is stirred at room temperature for 3 hours in hydrogen gas. 20 ml of water are added to the reaction mixture, and the catalyst is filtered off. The filtrate is evaporated to remove solvent. The residue is crystallized with methanol, whereby 290 mg of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline.5/4 H2 O are obtained.
M.p.: 233°-236° C. (decomp.).
[α]D 20 : -17.2° (C=0.5, H2 O).
IRνmax nujol (cm-1): 1715, 1680, 1630.
NMR (D2 O, δ): 1.7-2.4 (m, 4H), 2.6-3.9 (m, 6H), 3.03 (s, 3H), 4.0-4.45 (m, 2H), 4.95 (t, 1H), 7.27 (s, 1H), 8.57 (s, 1H).
(3) A mixture of 4.29 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-proline, 1.15 g of N-hydroxysuccinimide, 2.26 g of dicyclohexylcarbodiimide and 30 ml of dimethylformamide is stirred at 0° C. for 40 minutes and at room temperature for 80 minutes. 30 ml of 15% ammonia-methanol are then added to the mixture at 0° C., and the mixture is stirred at 0° C. for 30 minutes and at room temperature for one hour. Insoluble materials are filtered off, and the filtrate is evaporated to remove dimethylformamide. The residue is dissolved in 20 ml of water, and insoluble materials are again filtered off. The filtrate is adjusted to pH 8 with sodium bicarbonate and then passed through a column packed with CHP-20P resin. After the column is washed with 2 liters of water, the desired product is eluted with 10% methanol. The fractions which are positive to the Pauly’s reaction are collected and concentrated under reduced pressure. The residue is dissolved in 10 ml of water, and allowed to stand in a refrigerator. Crystalline precipitates are collected by filtration, washed with water, and then dried at 25° C. for one day, whereby 3.3 g of (1-methyl-L-4,5-dihydroorotyl)-L-histidyl-L-prolinamide.7/2 H2 O are obtained.
M.p.: 72°-75° C.
[α]D 25 : -13.6° (C=1, H2 O).
IRνmax nujol (cm-1): 3400, 3250, 1710, 1660, 1610, 1540.
- Fukuchi, I.; Asahi, T.; Kawashima, K.; Kawashima, Y.; Yamamura, M.; Matsuoka, Y.; Kinoshita, K. (1998). “Effects of taltirelin hydrate (TA-0910), a novel thyrotropin-releasing hormone analog, on in vivo dopamine release and turnover in rat brain”. Arzneimittel-Forschung 48 (4): 353–359. PMID 9608876.
- Asai, H.; Asahi, T.; Yamamura, M.; Yamauchi-Kohno, R.; Saito, A. (2005). “Lack of behavioral tolerance by repeated treatment with taltirelin hydrate, a thyrotropin-releasing hormone analog, in rats”. Pharmacology Biochemistry and Behavior 82 (4): 646–651. doi:10.1016/j.pbb.2005.11.004. PMID 16368129.
- Yamamura, M.; Suzuki, M.; Matsumoto, K. (1997). “Synthesis and pharmacological action of TRH analog peptide (Taltirelin)”. Nihon yakurigaku zasshi. Folia pharmacologica Japonica. 110 Suppl 1: 33P–38P. PMID 9503402.
- Urayama, A.; Yamada, S.; Kimura, R.; Zhang, J.; Watanabe, Y. (2002). “Neuroprotective effect and brain receptor binding of taltirelin, a novel thyrotropin-releasing hormone (TRH) analogue, in transient forebrain ischemia of C57BL/6J mice”. Life Sciences 72 (4–5): 601–607. doi:10.1016/S0024-3205(02)02268-3. PMID 12467901.
- Tanabe, M.; Tokuda, Y.; Takasu, K.; Ono, K.; Honda, M.; Ono, H. (2009). “The synthetic TRH analogue taltirelin exerts modality-specific antinociceptive effects via distinct descending monoaminergic systems”. British Journal of Pharmacology 150 (4): 403–414. doi:10.1038/sj.bjp.0707125. PMC 2189720. PMID 17220907.
- Takeuchi, Y.; Miyanomae, Y.; Komatsu, H.; Oomizono, Y.; Nishimura, A.; Okano, S.; Nishiki, T.; Sawada, T. (1994). “Efficacy of Thyrotropin-Releasing Hormone in the Treatment of Spinal Muscular Atrophy”. Journal of Child Neurology 9 (3): 287–289. doi:10.1177/088307389400900313. PMID 7930408.
- Tzeng, A. C.; Cheng, J.; Fryczynski, H.; Niranjan, V.; Stitik, T.; Sial, A.; Takeuchi, Y.; Foye, P.; Deprince, M.; Bach, J. R. (2000). “A study of thyrotropin-releasing hormone for the treatment of spinal muscular atrophy: A preliminary report”. American journal of physical medicine & rehabilitation / Association of Academic Physiatrists 79 (5): 435–440. doi:10.1097/00002060-200009000-00005. PMID 10994885.
- Kato, Z.; Okuda, M.; Okumura, Y.; Arai, T.; Teramoto, T.; Nishimura, M.; Kaneko, H.; Kondo, N. (2009). “Oral Administration of the Thyrotropin-Releasing Hormone (TRH) Analogue, Taltireline Hydrate, in Spinal Muscular Atrophy”. Journal of Child Neurology 24 (8): 1010–1012. doi:10.1177/0883073809333535. PMID 19666885.
EP 168 042 (Tanabe Seiyaku; appl. 10.7.1985; GB
JP 62 234 029 (Tanabe Seiyaku; J-prior. 27.12.1985).
Suzuki, M. et al.: J. Med. Chem. (JMCMAR) 33 (8), 2130-2137 (1990).