Cipralisant

Cipralisant (GT-2331, tentative trade name Perceptin) is an extremely potent histamine H3 receptor ligand originally developed by Gliatech.[1] Cipralisant was initially classified as a selective H3 antagonist,[2] but newer research (2005) suggests also agonist properties, i. e. functional selectivity.[3] Cipralisant seemed to be well tolerated during early testing, entering Phase II trials for ADHD in 2000.[4]

Cipralisant
Clinical data
ATC code
  • none
Identifiers
IUPAC name
  • 5-[(1S,2S)-2-(5,5-dimethylhex-1-ynyl)cyclopropyl]-1H-imidazole
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC14H20N2
Molar mass216.328 g·mol−1
3D model (JSmol)
SMILES
  • CC(C)(C)CCC#C[C@H]1C[C@@H]1c2cnc[nH]2
InChI
  • InChI=1S/C14H20N2/c1-14(2,3)7-5-4-6-11-8-12(11)13-9-15-10-16-13/h9-12H,5,7-8H2,1-3H3,(H,15,16)/t11-,12-/m0/s1 N
  • Key:CVKJAXCQPFOAIN-RYUDHWBXSA-N N
 NY (what is this?)  (verify)

The relatively recent cloning of human H3 receptor, as well as the discovery of its constitutive activity provided the ability to better assess the activity of H3 receptor ligands. Consequently, cipralisant was reassessed as an H3 receptor agonist in human and rat recombinant systems, showing functional selectivity and stimulating one type of G-protein coupled pathway while failing to activate other intracellular pathways.[3]

Gliatech filed for bankruptcy in 2002, and its intellectual property was inherited by Merck. The development of cipralisant seems to have been suspended since 2003 but research is ongoing, and recently it has been shown that it is the (1S,2S)-enantiomer which is the biologically active one.[5]

References
  1. Ito, Sayaka; Yoshimoto, Ryo; Miyamoto, Yasuhisa; Mitobe, Yuko; Nakamura, Takao; Ishihara, Akane; MacNeil, Douglas J.; Kanatani, Akio; Tokita, Shigeru (2006). "Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor". European Journal of Pharmacology. 529 (1–3): 40–46. doi:10.1016/j.ejphar.2005.10.066. PMID 16316645.
  2. Tedford CE, Hoffmann M, Seyedi N, et al. (June 1998). "High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models". Eur. J. Pharmacol. 351 (3): 307–311. doi:10.1016/S0014-2999(98)00396-3. PMID 9721022.
  3. Krueger, KM; Witte, DG; Ireland-Denny, L; Miller, TR; Baranowski, JL; Buckner, S; Milicic, I; Esbenshade, TA; Hancock, AA (2005). "G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations". The Journal of Pharmacology and Experimental Therapeutics. 314 (1): 271–81. doi:10.1124/jpet.104.078865. PMID 15821027. S2CID 20470970.
  4. Evaluate group: Gliatech Announces Initiation of Perceptin Phase II Clinical Trial.
  5. Liu, Huaqing; Kerdesky, Francis A.; Black, Lawrence A.; Fitzgerald, Michael; Henry, Rodger; Esbenshade, Timothy A.; Hancock, Arthur A.; Bennani, Youssef L. (2003). "An Efficient Multigram Synthesis of the Potent Histamine H3 Antagonist GT-2331 and the Reassessment of the Absolute Configuration". The Journal of Organic Chemistry. 69 (1): 192–194. doi:10.1021/jo035264t. ISSN 0022-3263. PMID 14703397.


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