Chemistry:EXP-561
EXP-561[1] is an investigational drug that acts as an inhibitor of the reuptake of serotonin, dopamine, and norepinephrine.[2][3][4][5] It was developed in the 1960s by Du Pont[6] and was suggested as a potential antidepressant but failed in trials[7] and was never marketed.[5][8][9][10]
SAR simplification in the molecular structure leads to a compound called 4-Phenylcyclohexylamine [19992-45-1].[11] This is produced by reduction of the oxime of a commercially available compound that is called 4-phenylcyclohexanone. It is noteworthy to point out that this precursor might forseeably share a dual use in the synthesis of danavorexton.
In one method of synthesis, EXP-561 is made from a chemical that is called 3-carboethoxy-6-phenyl-2-pyrone [6465-14-1]. The disadvantage of this method is that it needed to be heated with ethylene in benzene solvent at 200C for 16 hours at 1000 atmospheres, so a suitable pressure vessel was needed. Although, alternative protocols were addressed that sought to circumvent this limitation.[12] However, this much pressure seemed excessive and a more recent patent only employed 75 bar pressure.
See also
References
- ↑ Snyder JA, "Pharmaceutical compositions and methods utilizing substituted bicyclo[2.2.2]-octanes", US patent 3362878, issued 9 January 1968, assigned to EIDP Inc.
- ↑ "Inhibition of amine uptake by 4-phenyl-bicyclo(2,2,2)octan-1-amine hydrochloride monohydrate (EXP 561) in rats". biochemical Pharmacology 25 (21): 2409–2410. November 1976. doi:10.1016/0006-2952(76)90039-3. PMID 999731.
- ↑ "Molecular geometry of inhibitors of the uptake of catecholamines and serotonin in synaptosomal preparations of rat brain". The Journal of Pharmacology and Experimental Therapeutics 199 (3): 649–661. December 1976. doi:10.1016/S0022-3565(25)30726-3. PMID 994022. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=994022.
- ↑ "Blockade of monoamine uptake by 1-amino-4-phenylbicyclo(2,2,2)octane (EXP 561) in rat brain and heart". Neuropharmacology 16 (1): 11–15. January 1977. doi:10.1016/0028-3908(77)90040-5. PMID 834358.
- ↑ 5.0 5.1 "Pharmacological properties of EXP 561, a potential antidepressant drug". Journal of Neural Transmission 70 (1–2): 81–97. 1987. doi:10.1007/BF01252511. PMID 2822850.
- ↑ Snyder JA, "4-Phenylbicyclo[2.2.2]octane-1-amines and salts thereof", US patent 3308160, issued 7 March 1967, assigned to EIDP Inc.
- ↑ "Theories of biological etiology of affective disorders". International Review of Neurobiology. 12. 1970. pp. 145–175. doi:10.1016/s0074-7742(08)60060-4. ISBN 978-0-12-366812-7.
- ↑ "A clinical-pharmacological study with EXP 561". Current Therapeutic Research, Clinical and Experimental 9 (6): 306–308. June 1967. PMID 4963065.
- ↑ "Non-correlation of preclinical-clinical evaluation of a prosposed anti-depressant 4-phenyl-bicyclo(2,2,2)octan-1-amine hydrochloride monohydrate (EXP 561)". Arzneimittel-Forschung 18 (2): 243–245. February 1968. PMID 5695389.
- ↑ "Inhibition of 3H-dopamine accumulation in reserpinized and normal rat striatum". Acta Pharmacologica et Toxicologica 44 (5): 329–335. May 1979. doi:10.1111/j.1600-0773.1979.tb02339.x. PMID 474143.
- ↑ "[Phenylcyclohexylamine and derivatives. IV. Salts of trans-4-phenylcyclohexylamine with -substituted 4-diphenyl- and 4-cyclohexylphenyl acetic acids and their pharmacological activity]". Il Farmaco; Edizione Scientifica 28 (4): 265–277. 1973. PMID 4698884.
- ↑ "Preparation of 4-substituted 1-methoxycarbonylbicyclo[2.2.2octanes, 4-substituted 1-phenylbicyclo[2.2.2]octanes, 4-substituted 1-p-nitrophenylbicyclo[2.2.2]octanes and 1,4-disubstituted bicyclo[2.2.2]octanes"]. The Journal of Organic Chemistry 35 (4): 917–923. April 1970. doi:10.1021/jo00829a010. https://pubs.acs.org/doi/abs/10.1021/jo00829a010.
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