Lu AA41063

Lu AA41063
Clinical data
Drug classAdenosine A2A receptor antagonist
Identifiers
  • 4-(3,3-dimethylbutanoylamino)-3,5-difluoro-N-(1,3-thiazol-2-yl)benzamide
CAS Number
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
FormulaC16H17F2N3O2S
Molar mass353.39 g·mol−1
3D model (JSmol)
  • CC(C)(C)CC(=O)NC1=C(C=C(C=C1F)C(=O)NC2=NC=CS2)F
  • InChI=1S/C16H17F2N3O2S/c1-16(2,3)8-12(22)20-13-10(17)6-9(7-11(13)18)14(23)21-15-19-4-5-24-15/h4-7H,8H2,1-3H3,(H,20,22)(H,19,21,23)
  • Key:KEUJAGGJGBWRFC-UHFFFAOYSA-N

Lu AA41063 is a selective adenosine A2A receptor antagonist.[1][2][3][4][5] Structurally, it is a non-xanthine.[2]

The affinities (Ki) of the drug for the human adenosine receptors are 5.9 nM for the adenosine A2A receptor, 410 nM for the adenosine A1 receptor (69-fold lower than for the A2A receptor), 260 nM for the adenosine A2B receptor (44-fold lower than for the A2A receptor), and >10,000 nM for the adenosine A3 receptor (>1,695-fold lower than for the A2A receptor).[2]

Lu AA41063 was first described in the scientific literature by 2014.[1][5]

Lu AA47070, a water-soluble phosphate ester prodrug of Lu AA41063, is orally active and was under development for the treatment of Parkinson's disease but was discontinued.[6][1][2][7][8] In addition to its antiparkinsonian-like effects, Lu AA47070 reverses motivational deficits in animals and hence shows pro-motivational effects.[9][10][11]

References

  1. ^ a b c Yuan G, Jones GB (2014). "Towards next generation adenosine A(2A) receptor antagonists". Curr Med Chem. 21 (34): 3918–3935. doi:10.2174/0929867321666140826115123. PMID 25174927.
  2. ^ a b c d Müller, Christa E. (2015). "Adenosine A2A Receptor Antagonists in Drug Development". The Adenosinergic System. Current Topics in Neurotoxicity. Vol. 10. Cham: Springer International Publishing. pp. 39–56. doi:10.1007/978-3-319-20273-0_3. ISBN 978-3-319-20272-3.
  3. ^ Al-Attraqchi OH, Attimarad M, Venugopala KN, Nair A, Al-Attraqchi NH (2019). "Adenosine A2A Receptor as a Potential Drug Target - Current Status and Future Perspectives". Curr Pharm Des. 25 (25): 2716–2740. doi:10.2174/1381612825666190716113444. PMID 31333093.
  4. ^ Zheng J, Zhang X, Zhen X (February 2019). "Development of Adenosine A2A Receptor Antagonists for the Treatment of Parkinson's Disease: A Recent Update and Challenge". ACS Chem Neurosci. 10 (2): 783–791. doi:10.1021/acschemneuro.8b00313. PMID 30199223.
  5. ^ a b Mikkelsen GK, Langgård M, Schrøder TJ, Kreilgaard M, Jørgensen EB, Brandt G, Griffon Y, Boffey R, Bang-Andersen B (March 2015). "Synthesis and SAR studies of analogues of 4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-N-thiazol-2-yl-benzamide (Lu AA41063) as adenosine A2A receptor ligands with improved aqueous solubility". Bioorg Med Chem Lett. 25 (6): 1212–1216. doi:10.1016/j.bmcl.2015.01.062. PMID 25701253.
  6. ^ IJzerman AP, Jacobson KA, Müller CE, Cronstein BN, Cunha RA (April 2022). "International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update". Pharmacological Reviews. 74 (2): 340–372. doi:10.1124/pharmrev.121.000445. PMC 8973513. PMID 35302044.
  7. ^ Sams AG, Mikkelsen GK, Larsen M, Langgård M, Howells ME, Schrøder TJ, et al. (February 2011). "Discovery of phosphoric acid mono-{2-[(E/Z)-4-(3,3-dimethyl-butyrylamino)-3,5-difluoro-benzoylimino]-thiazol-3-ylmethyl} ester (Lu AA47070): a phosphonooxymethylene prodrug of a potent and selective hA(2A) receptor antagonist". Journal of Medicinal Chemistry. 54 (3): 751–764. doi:10.1021/jm1008659. PMID 21210664.
  8. ^ "LU AA 47070". AdisInsight. Springer Nature Switzerland AG. 18 May 2009. Retrieved 22 September 2024.
  9. ^ Sachdeva S, Gupta M (July 2013). "Adenosine and its receptors as therapeutic targets: An overview". Saudi Pharmaceutical Journal. 21 (3): 245–253. doi:10.1016/j.jsps.2012.05.011. PMC 3744929. PMID 23960840. Antagonists of the A2A subtype of adenosine receptor have emerged as a leading candidate class of nondopaminergic antiparkinsonian agents (Feigin, 2003). The ability of Lu AA47070, adenosine A2A antagonist to reverse the effects of D2 receptor blockade suggests that this compound could have potential utility as a treatment for parkinsonism, and for some of the motivational symptoms of depression. In the adult male Sprague Dawley rats the tremulous jaw movements induced by subchronic administration of the DA D2 antagonist pimozide were reversed by Lu AA47070. Lu AA47070 was also able to reverse the catalepsy induced by subchronic administration of the D2 antagonist pimozide and it also reverse the locomotor suppression induced by subchronic administration of the D2 antagonist pimozide (Collins et al., 2012).
  10. ^ Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacological Reviews. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.
  11. ^ Collins LE, Sager TN, Sams AG, Pennarola A, Port RG, Shahriari M, Salamone JD (January 2012). "The novel adenosine A2A antagonist Lu AA47070 reverses the motor and motivational effects produced by dopamine D2 receptor blockade". Pharmacology, Biochemistry, and Behavior. 100 (3): 498–505. doi:10.1016/j.pbb.2011.10.015. PMID 22037410.


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