Armesocarb

Armesocarb
Clinical data
Other names(R)-Mesocarb; L-Mesocarb; MLR-1019; MLR1019
Drug classAtypical dopamine reuptake inhibitor
Identifiers
  • N-phenyl-N'-[3-[(2R)-1-phenylpropan-2-yl]oxadiazol-3-ium-5-yl]carbamimidate
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
FormulaC18H18N4O2
Molar mass322.368 g·mol−1
3D model (JSmol)
  • C[C@H](CC1=CC=CC=C1)[N+]2=NOC(=C2)N=C(NC3=CC=CC=C3)[O-]
  • InChI=1S/C18H18N4O2/c1-14(12-15-8-4-2-5-9-15)22-13-17(24-21-22)20-18(23)19-16-10-6-3-7-11-16/h2-11,13-14H,12H2,1H3,(H-,19,20,21,23)/t14-/m1/s1
  • Key:OWFUPROYPKGHMH-CQSZACIVSA-N

Armesocarb (developmental code name MLR-1019), also known as (R)-mesocarb or L-mesocarb, is a selective atypical dopamine reuptake inhibitor (DRI). It is currently under development for the treatment of Parkinson's disease and sleep disorders.[1][2]

It is the active (R)-enantiomer of the formerly clinically used stimulant-like drug mesocarb (MLR-1017; brand name Sydnocarb).[1][2][3]

Pharmacology

Mesocarb is known to be a highly selective DRI.[2] However, in 2021, it was discovered that mesocarb is not a conventional DRI but acts as a dopamine transporter (DAT) allosteric modulator or non-competitive inhibitor.[4][5][6]

In accordance with its nature as an atypical DAT blocker, the drug exhibits atypical effects compared to conventional DRIs.[4][5][6][2] For example, mesocarb shows greater antiparkinsonian activity in animals compared to other DRIs.[2]

Mesocarb has wakefulness-promoting effects in animals.[2][7] Armesocarb, as the active enantiomer of mesocarb, shows greater therapeutic potency than the racemic form in animals.[1][2][3] In contrast, the (S)- or D-enantiomer of mesocarb is virtually inactive in animal behavioral tests.[3]

History

Armesocarb was first described in the scientific literature as an enantiopure compound by 2005 and again in 2017.[3][2]

Clinical studies

As of April 2023, armesocarb is undergoing phase 1 clinical trials for Parkinson's disease and is in preclinical development for sleep disorders.[1] The latter indication may specifically target excessive daytime sleepiness (EDS) in people with Parkinson's disease.[2] Armesocarb is also in development for the treatment of levodopa-induced dyskinesia.[8][2]

See also

References

  1. ^ a b c d "Melior Pharmaceuticals". AdisInsight. 28 April 2023. Retrieved 26 September 2024.
  2. ^ a b c d e f g h i j Macolino-Kane CM, Ciallella JR, Lipinski CA, Reaume AG (14 July 2017). "Phenotypic Screening". Drug Repositioning. Frontiers in Neurotherapeutics. Boca Raton: CRC Press. pp. 121–145. doi:10.4324/9781315373669-7. ISBN 978-1-315-37366-9.
  3. ^ a b c d Al'tshuler RA (2005). "Comparative Molecular Model Estimation of the Affinity of Phenylethylamines to the Binding Sites of Membrane Transporters". Pharmaceutical Chemistry Journal. 39 (4): 169–175. doi:10.1007/s11094-005-0110-3. ISSN 0091-150X.
  4. ^ a b Nepal B, Das S, Reith ME, Kortagere S (2023). "Overview of the structure and function of the dopamine transporter and its protein interactions". Frontiers in Physiology. 14: 1150355. doi:10.3389/fphys.2023.1150355. PMC 10020207. PMID 36935752.
  5. ^ a b Nguyen H, Cheng MH, Lee JY, Aggarwal S, Mortensen OV, Bahar I (2024). "Allosteric modulation of serotonin and dopamine transporters: New insights from computations and experiments". Current Research in Physiology. 7: 100125. doi:10.1016/j.crphys.2024.100125. PMC 11148570. PMID 38836245.
  6. ^ a b Aggarwal S, Cheng MH, Salvino JM, Bahar I, Mortensen OV (June 2021). "Functional Characterization of the Dopaminergic Psychostimulant Sydnocarb as an Allosteric Modulator of the Human Dopamine Transporter". Biomedicines. 9 (6): 634. doi:10.3390/biomedicines9060634. PMC 8227285. PMID 34199621.
  7. ^ Gruner JA, Mathiasen JR, Flood DG, Gasior M (May 2011). "Characterization of pharmacological and wake-promoting properties of the dopaminergic stimulant sydnocarb in rats". The Journal of Pharmacology and Experimental Therapeutics. 337 (2): 380–390. doi:10.1124/jpet.111.178947. PMID 21300706.
  8. ^ AlShimemeri S, Fox SH, Visanji NP (June 2020). "Emerging drugs for the treatment of L-DOPA-induced dyskinesia: an update". Expert Opinion on Emerging Drugs. 25 (2): 131–144. doi:10.1080/14728214.2020.1763954. PMID 32366130.