Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-<scp>l</scp>-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

Kobayashi, Naotake; Satô, Norihito; Fujimura, Yuko; Kihara, Tsuyoshi; Sugita, Katsuji; Takahashi, Kouji; Koike, Katsumi; Sugawara, Tamio; Tada, Yukio; Nakai, Hiroshi; Yoshikawa, Tomohiro

doi:10.1021/acsomega.8b01481

Cited by 12 publications

(10 citation statements)

References 79 publications

(98 reference statements)

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“…Two main directions have been explored to harness the beneficial effects of the peptide in the CNS, while overcoming limitations of its direct delivery from the circulation. One approach has focused on creating analogs with diminished neuroendocrine activity, as well as increased metabolic stability and oral bioavailability [8,9,10]. Among these analogs, taltirelin has been approved in Japan for human therapy against spinocerebellar ataxia [10].…”

Section: Introductionmentioning

confidence: 99%

Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

et al. 2019

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Using thyrotropin-releasing hormone (TRH) as a model, we explored whether synergistic combination of lipoamino acid(s) and a linker cleaved by prolyl oligopeptidase (POP) can be used as a promoiety for prodrug design for the preferential brain delivery of the peptide. A representative prodrug based on this design principle was synthesized, and its membrane affinity and in vitro metabolic stability, with or without the presence of a POP inhibitor, were studied. The in vivo formation of TRH from the prodrug construct was probed by utilizing the antidepressant effect of the peptide, as well as its ability to increase acetylcholine (ACh) synthesis and release. We found that the prototype prodrug showed excellent membrane affinity and greatly increased metabolic stability in mouse blood and brain homogenate compared to the parent peptide, yet a POP inhibitor completely prevented prodrug metabolism in brain homogenate. In vivo, administration of the prodrug triggered antidepressant-like effect, and microdialysis sampling showed greatly increased ACh release that was also antagonized upon a POP inhibitor treatment. Altogether, the obtained promising exploratory data warrant further investigations on the utility of the prodrug approach introduced here for brain-enhanced delivery of small peptides with neurotherapeutic potential.

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Section: Introductionmentioning

confidence: 99%

Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

et al. 2019

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“…Rovatirelin (1-{N-[(4S,5S)-(5-methyl-2-oxooxazolidin-4-yl)carbonyl]-3-(thiazol-4-yl)-L-alanyl}-(2R)-2-methylpyrrolidine trihydrate) has a higher affinity for TRH-R1 (Ki = 702 nM) than Taltirelin (Ki = 3,880 nM) but still lower than TRH (Ki = 128 nM) in cell membrane preparation from CHO-K1 cells overexpressing the human TRH receptor (Ijiro et al, 2015). Rovatirelin is resistant to thyroliberinase in rat plasma and also to TRH-DE in pituitary (Kobayashi et al, 2018;Kobayashi et al, 2019a;Kobayshi et al, 2019b).…”

Section: Trh Analogues Resistant To Hydrolysismentioning

confidence: 96%

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

et al. 2020

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Thyrotropin releasing hormone (TRH: Glp-His-Pro-NH 2) is a peptide mainly produced by brain neurons. In mammals, hypophysiotropic TRH neurons of the paraventricular nucleus of the hypothalamus integrate metabolic information and drive the secretion of thyrotropin from the anterior pituitary, and thus the activity of the thyroid axis. Other hypothalamic or extrahypothalamic TRH neurons have less understood functions although pharmacological studies have shown that TRH has multiple central effects, such as promoting arousal, anorexia and anxiolysis, as well as controlling gastric, cardiac and respiratory autonomic functions. Two G-protein-coupled TRH receptors (TRH-R1 and TRH-R2) transduce TRH effects in some mammals although humans lack TRH-R2. TRH effects are of short duration, in part because the peptide is hydrolyzed in blood and extracellular space by a M1 family metallopeptidase, the TRH-degrading ectoenzyme (TRH-DE), also called pyroglutamyl peptidase II. TRH-DE is enriched in various brain regions but is also expressed in peripheral tissues including the anterior pituitary and the liver, which secretes a soluble form into blood. Among the M1 metallopeptidases, TRH-DE is the only member with a very narrow specificity; its best characterized biological substrate is TRH, making it a target for the specific manipulation of TRH activity. Two other substrates of TRH-DE, Glp-Phe-Pro-NH 2 and Glp-Tyr-Pro-NH 2, are also present in many tissues. Analogs of TRH resistant to hydrolysis by TRH-DE have prolonged central efficiency. Structure-activity studies allowed the identification of residues critical for activity and specificity. Research with specific inhibitors has confirmed that TRH-DE controls TRH actions. TRH-DE expression by b2-tanycytes of the median eminence of the hypothalamus allows the control of TRH flux into the hypothalamus-pituitary portal vessels and may regulate serum thyrotropin secretion. In this review we describe the critical evidences that suggest that modification of TRH-DE activity in tanycytes, and/or in other brain regions, may generate beneficial consequences in some central and metabolic disorders and identify potential drawbacks and missing information needed to test these hypotheses.

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“…Purification of the residue via flash column chromatography (EtOAc:n-hexane = 1:5) afforded bromopropanal 3 (178 mg, 60%) as a colorless oil. 1 To a solution of bromopropanal 3 (30 mg, 0.079 mmol) in dimethylformamide (1 mL) was added thioformamide [10] (5.3 mg, 0.087 mmol) at ambient temperature. After being stirred at 60 • C for 3 h, the reaction mixture was diluted with EtOAc, and quenched with a saturated NaHCO 3 solution.…”

Section: -(4-(benzyloxy)-35-dimethoxyphenyl)-2-bromopropanal (3)mentioning

confidence: 99%

Synthesis and Structural Confirmation of the Thiazole Alkaloids Derived from Peganum harmala L.

Sim

Han

2021

Applied Sciences

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Peganumal A and B are thiazole alkaloids isolated from the seeds of Peganum harmala L. Thiazole moieties are rarely found in natural products, but diverse compounds possessing thiazole moieties have attracted attention owing to their broad range of biological activities. Peganumals are the first natural thiazole compounds isolated from the genus Peganum. It was difficult to define the exact structure of peganumal A via spectroscopic analysis. In this paper, we report the first total synthesis of peganumal A and B. The 5-benzylthiazole skeleton possessing methyl or hydrogen at the 2-position of the peganumals was efficiently constructed via the Hantzsch thiazole synthesis of the α-bromoaldehyde intermediate. Moreover, the spectral data of the synthetic 2H–thiazole compound were identical to those previously reported for peganumal A. The synthesis allowed the confirmation of the structure of peganumal A.

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Discovery of the Orally Effective Thyrotropin-Releasing Hormone Mimetic: 1-{N-[(4S,5S)-(5-Methyl-2-oxooxazolidine-4-yl)carbonyl]-3-(thiazol-4-yl)-l-alanyl}-(2R)-2-methylpyrrolidine Trihydrate (Rovatirelin Hydrate)

Cited by 12 publications

References 79 publications

Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

Brain Delivery of Thyrotropin-Releasing Hormone via a Novel Prodrug Approach

The Thyrotropin-Releasing Hormone-Degrading Ectoenzyme, a Therapeutic Target?

Synthesis and Structural Confirmation of the Thiazole Alkaloids Derived from Peganum harmala L.

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