Montirelin

Montirelin
Clinical data
Other names	CG 3703, CG-3703, CNK 602A, CNK 603, CNK-602A, CNK-603, NS-3.
Identifiers
	IUPAC name (3R,6R)-N-[(2S)-1-[(2S)-2-carbamoylpyrrolidin-1-yl]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]-6-methyl-5-oxothiomorpholine-3-carboxamide;
CAS Number	90243-66-6 62305-91-3;
PubChem CID	6917793;
DrugBank	DB19762;
ChemSpider	5293019;
UNII	30MUJ6YYUY;
KEGG	D02588;
ChEBI	CHEBI:31864;
Chemical and physical data
Formula	C17H24N6O4S
Molar mass	408.48 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES 1S/C17H24N6O4S/c1-9-15(25)22-12(7-28-9)16(26)21-11(5-10-6-19-8-20-10)17(27)23-4-2-3-13(23)14(18)24/h6,8-9,11-13H,2-5,7H2,1H3,(H2,18,24)(H,19,20)(H,21,26)(H,22,25)/t9-,11+,12+,13+/m1/s1;
	InChI InChI=C[C@@H]1C(=O)N[C@@H](CS1)C(=O)N[C@@H](CC2=CN=CN2)C(=O)N3CCC[C@H]3C(=O)N; Key:RSHMQGIMHQPMEB-IXOXFDKPSA-N;

Montirelin (also known as CG-3703 or NS-3) is a synthetic analogue of thyrotropin-releasing hormone (TRH), designed to enhance central nervous system stimulation with greater potency and duration than natural TRH.^[1]

Montirelin binds to TRH receptors in the brain, stimulating the release of thyrotropin (TSH) and prolactin. It exhibits sustained receptor occupancy and a counter-clockwise hysteresis between plasma concentration and receptor binding, suggesting prolonged CNS activity.

Montirelin has demonstrated efficacy in animal models for:^[2]^[3]

Concussion-induced unconsciousness
Cerebral ischemia
Memory disruption
Narcolepsy and cataplexy
Seizures and spontaneous convulsions
Spinal trauma

In human studies, a 0.5 mg dose administered over 14 days improved consciousness in 73% of patients with neurological disturbances. Its ability to stimulate cholinergic and noradrenergic systems suggests promise in treating cognitive dysfunction and sleep disorders. Although it the patent, it said that the strength of the medicine was 4mg per tablet, but in contrast to TRH it can be administered orally and is more resistant to metabolic degradation.^[1]

Synthesis

Synthesis:^[4]^[5] Patent (Ex 10):^[6] (CD)

The catalytic hydrogenation of (S)-1-N-Cbz-prolinamide [34079-31-7] (1) gives L-Prolinamide [7531-52-4] (2). This is condensed with Z-His-NHNH2 [49706-31-2] (3) in the presence of nitrous acid to give Benzyloxycarbonyl-L-histidyl-L-prolineamide, PC13229382^[7] (4). The protecting group is hydrolyzed in acid to give His-pro-amide [33605-69-5] (5). This is finally condensed with (3R,6R)-6-Methyl-5-oxothiomorpholine-3-carboxylic acid, PC99645792^[8] (6) in the presence of by of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide, completing the synthesis of Montirelin (7).

Other TRH analogues

Analogues of TRH is not just limited to montirelin. Other agents to consider include the following:

DN-1417 [77026-80-3]
JTP 2942 [148152-77-6]
RX-77368 [76820-40-1]
Orotirelin [62305-86-6]

References

^ ^a ^b US 4956364, Kimura K, Ukai Y, Ogasawara T, Nakagawa Y, "Nootropic agent", issued 11 September 1990, assigned to Gruenenthal GmbH
^ Clarke KA, Kirby K (January 1994). "Stimulation of locomotion in neonate rats by TRH analogue CG3703". Neuropeptides. 26 (1): 71–5. doi:10.1016/0143-4179(94)90096-5. PMID 8159287.
^ Itoh Y, Sugimoto T, Ukai Y, Morino A, Kimura K (October 1995). "Permeability of NS-3, a thyrotropin-releasing hormone analogue, into the brain after its systemic administration in rats: a microdialysis study". The Journal of Pharmacy and Pharmacology. 47 (10): 833–6. doi:10.1111/j.2042-7158.1995.tb05750.x. PMID 8583352.
^ Bauce LG, Goren HJ (1979). "Synthesis of a series of residue 1 (pyroglutamic acid) analogs of thyrotrophin releasing hormone". International Journal of Peptide and Protein Research. 14 (3): 216–26. doi:10.1111/j.1399-3011.1979.tb01928.x. PMID 118133.
^ Pento JT (1983). "CG-3703". Drugs of the Future. 8 (12): 1007. doi:10.1358/dof.1983.008.12.75170. ISSN 0377-8282.
^ US 4045556, Schwertner E, Herrling S, "Dipeptide derivatives, process for manufacture and pharmaceutical preparation", issued 10 August 1977-08, assigned to Gruenenthal GmbH
^ "Benzyloxycarbonyl-L-histidyl-L-prolineamide". PubMed. U.S. National Library of Medicine.
^ "(3R,6R)-6-Methyl-5-oxothiomorpholine-3-carboxylic acid". PubMed. U.S. National Library of Medicine.

[nootropic-1] US 4956364, Kimura K, Ukai Y, Ogasawara T, Nakagawa Y, "Nootropic agent", issued 11 September 1990, assigned to Gruenenthal GmbH

[pmid8159287-2] Clarke KA, Kirby K (January 1994). "Stimulation of locomotion in neonate rats by TRH analogue CG3703". Neuropeptides. 26 (1): 71–5. doi:10.1016/0143-4179(94)90096-5. PMID 8159287.

[pmid8583352-3] Itoh Y, Sugimoto T, Ukai Y, Morino A, Kimura K (October 1995). "Permeability of NS-3, a thyrotropin-releasing hormone analogue, into the brain after its systemic administration in rats: a microdialysis study". The Journal of Pharmacy and Pharmacology. 47 (10): 833–6. doi:10.1111/j.2042-7158.1995.tb05750.x. PMID 8583352.

[pmid118133-4] Bauce LG, Goren HJ (1979). "Synthesis of a series of residue 1 (pyroglutamic acid) analogs of thyrotrophin releasing hormone". International Journal of Peptide and Protein Research. 14 (3): 216–26. doi:10.1111/j.1399-3011.1979.tb01928.x. PMID 118133.

[5] Pento JT (1983). "CG-3703". Drugs of the Future. 8 (12): 1007. doi:10.1358/dof.1983.008.12.75170. ISSN 0377-8282.

[6] US 4045556, Schwertner E, Herrling S, "Dipeptide derivatives, process for manufacture and pharmaceutical preparation", issued 10 August 1977-08, assigned to Gruenenthal GmbH

[7] "Benzyloxycarbonyl-L-histidyl-L-prolineamide". PubMed. U.S. National Library of Medicine.

[8] "(3R,6R)-6-Methyl-5-oxothiomorpholine-3-carboxylic acid". PubMed. U.S. National Library of Medicine.

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