2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid
Meclinertant (SR-48692) is a drug which acts as a selective, non-peptide antagonist at the neurotensin receptor NTS1, and was the first non-peptide antagonist developed for this receptor.[1][2] It is used in scientific research to explore the interaction between neurotensin and other neurotransmitters in the brain,[3][4][5][6][7][8] and produces anxiolytic, anti-addictive and memory-impairing effects in animal studies.[9][10][11][12]
PatentSubmittedGranted1-(7-chloroquinolin-4-yl)pyrazole-3-carboxamide N-oxide derivatives, method of preparing them, and their pharmaceutical compositions [US5561234]1996-10-01
Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin [US5585497]1996-12-17
3-amidopyrazole derivatives, process for preparing these and pharmaceutical composites containing them [US5420141]1995-05-30
Substituted 1-naphthyl-3-pyrazolecarboxamides which are active on neurotensin, their preparation and pharmaceutical compositions containing them [US5523455]1996-06-04
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5607958]1997-03-04
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5616592]1997-04-01
3-amidopyrazole derivatives, process for preparing these and pharmaceutical compositions containing them [US5635526]1997-06-03
Substituted 1-phenyl-3-pyrazolecarboxamides active on neurotensin receptors, their preparation and pharmaceutical compositions containing them [US5965579]1999-10-12
| Systematic (IUPAC) name | |
|---|---|
| 2-([1-(7-Chloro-4-quinolinyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole-3-carbonyl]amino)admantane-2-carboxylic acid | |
| Clinical data | |
| Legal status |
?
|
| Identifiers | |
| CAS number | 146362-70-1  |
| ATC code | ? |
| PubChem | CID 119192 |
| IUPHAR ligand | 1582 |
| UNII | 5JBP4SI96H |
| Chemical data | |
| Formula | C32H31ClN4O5 |
| Mol. mass | 587.064 |
A Machine-Assisted Flow Synthesis of SR48692: A Probe for the Investigation of Neurotensin Receptor-1 (pages 7917–7930)
Dr. Claudio Battilocchio, Benjamin J. Deadman, Dr. Nikzad Nikbin, Dr. Matthew O. Kitching, Prof. Ian R. Baxendale and Prof. Steven V. Ley
Article first published online: 16 APR 2013 | DOI: 10.1002/chem.201300696
Flow and pharmaceuticals? An investigation into whether machine-assisted technologies can be of true help in the multistep synthesis of a potent neurotensin receptor-1 probe, Meclinertant (SR48692; see structure), is reported.
Meclinertant (SR 48692)
We developed an improved synthesis of the neurotensin antagonist biological probe SR 48692. The preparation includes an number of chemical conversions and strategies involving the use of flow chemistry platforms which helped overcome some of the limiting synthetic transformations in the original chemical route .
Meclinertant (SR 48692): The synthesis of neurotensin antagonist SR 48692 for prostate cancer research I.R. Baxendale, S. Cheung, M.O. Kitching, S.V. Ley, J.W. Shearman Bio. Org. Med. Chem. 2013, 21, 4378-4387.
A synthesis of the neurotensin 1 receptor probe Merclinertant (SR48692) has been reported using a range of continuous flow through synthesis, in-line reaction monioring and purification techniques. This strategy has been contrasted with a more conventional batch synthesis approach.
Notably the safe use of phosgene gas (generated in situ), the superheating of solvents to accelerate reaction rates, the processing of a reagent suspension under continuous flow-through conditions and the application of semi-permeable membrane technology to facilitate work-up and purification were all techniques that could be beneficially applied in the synthetic scheme.
Abstract:
Meclinertant, Reminertant, SR-48692
The condensation of 2′,6′-dimethoxyacetophenone (I) with diethyl oxalate (II) by means of sodium methoxide in refluxing methanol gives the dioxobutyrate (III), which is cyclized with 7-chloroquinoline-4-hydrazine (IV) in refluxing acetic acid yielding the pyrazole derivative (V). The hydrolysis of the ester group of (V) with KOH in refluxing methanol/water affords the corresponding carboxylic acid (VI), which is finally treated with SOCl2 in refluxing toluene and condensed with 2-aminoadamantane-2-carboxylic acid.
EP 0477049; FR 2665898; JP 1992244065; US 5420141; US 5607958; US 5616592; US 5635526; US 5744491; US 5744493
…………………………….
- Gully D, Canton M, Boigegrain R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A (January 1993).“Biochemical and pharmacological profile of a potent and selective nonpeptide antagonist of the neurotensin receptor”. Proceedings of the National Academy of Sciences of the United States of America 90 (1): 65–9. doi:10.1073/pnas.90.1.65. PMC 45600. PMID 8380498.
- Gully D, Jeanjean F, Poncelet M, Steinberg R, Soubrié P, Le Fur G, Maffrand JP (1995). “Neuropharmacological profile of non-peptide neurotensin antagonists”. Fundamental & Clinical Pharmacology 9 (6): 513–21. doi:10.1111/j.1472-8206.1995.tb00528.x.PMID 8808171.
- Rostene W, Azzi M, Boudin H, Lepee I, Souaze F, Mendez-Ubach M, Betancur C, Gully D (April 1997). “Use of nonpeptide antagonists to explore the physiological roles of neurotensin. Focus on brain neurotensin/dopamine interactions”. Annals of the New York Academy of Sciences 814: 125–41. doi:10.1111/j.1749-6632.1997.tb46151.x. PMID 9160965.
- Jump up^ Jolas T, Aghajanian GK (August 1997). “Neurotensin and the serotonergic system”. Progress in Neurobiology 52 (6): 455–68.doi:10.1016/S0301-0082(97)00025-7. PMID 9316156.
- Jump up^ Dobner PR, Deutch AY, Fadel J (June 2003). “Neurotensin: dual roles in psychostimulant and antipsychotic drug responses”. Life Sciences73 (6): 801–11. doi:10.1016/S0024-3205(03)00411-9. PMID 12801600.
- Jump up^ Chen L, Yung KK, Yung WH (September 2006). “Neurotensin selectively facilitates glutamatergic transmission in globus pallidus”.Neuroscience 141 (4): 1871–8. doi:10.1016/j.neuroscience.2006.05.049. PMID 16814931.
- Petkova-Kirova P, Rakovska A, Della Corte L, Zaekova G, Radomirov R, Mayer A (September 2008). “Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis”. Brain Research Bulletin 77 (2–3): 129–35. doi:10.1016/j.brainresbull.2008.04.003. PMID 18721670.
- Petkova-Kirova P, Rakovska A, Zaekova G, Ballini C, Corte LD, Radomirov R, Vágvölgyi A (December 2008). “Stimulation by neurotensin of dopamine and 5-hydroxytryptamine (5-HT) release from rat prefrontal cortex: possible role of NTR1 receptors in neuropsychiatric disorders”.Neurochemistry International 53 (6–8): 355–61. doi:10.1016/j.neuint.2008.08.010. PMID 18835308.
- Griebel G, Moindrot N, Aliaga C, Simiand J, Soubrié P (December 2001). “Characterization of the profile of neurokinin-2 and neurotensin receptor antagonists in the mouse defense test battery”. Neuroscience and Biobehavioral Reviews 25 (7–8): 619–26. doi:10.1016/S0149-7634(01)00045-8. PMID 11801287.
- Tirado-Santiago G, Lázaro-Muñoz G, Rodríguez-González V, Maldonado-Vlaar CS (October 2006). “Microinfusions of neurotensin antagonist SR 48692 within the nucleus accumbens core impair spatial learning in rats”. Behavioral Neuroscience 120 (5): 1093–102. doi:10.1037/0735-7044.120.5.1093. PMID 17014260.
- Felszeghy K, Espinosa JM, Scarna H, Bérod A, Rostène W, Pélaprat D (December 2007). “Neurotensin receptor antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference”. Neuropsychopharmacology 32 (12): 2601–10. doi:10.1038/sj.npp.1301382. PMC 2992550. PMID 17356568.
- Lévesque K, Lamarche C, Rompré PP (October 2008). “Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine”.European Journal of Pharmacology 594 (1–3): 132–8. doi:10.1016/j.ejphar.2008.07.048. PMID 18706409.
Sorry, the comment form is closed at this time.