Aptiganel

Aptiganel
Clinical data
ATC code
  • none
Legal status
Legal status
  • In general: uncontrolled
Identifiers
IUPAC name
  • 1-(3-ethylphenyl)-1-methyl-2-naphthalen-1-ylguanidine
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC20H21N3
Molar mass303.409 g·mol−1
3D model (JSmol)
SMILES
  • CCC1=CC(=CC=C1)N(C)C(=NC2=CC=CC3=CC=CC=C32)N
InChI
  • InChI=1S/C20H21N3/c1-3-15-8-6-11-17(14-15)23(2)20(21)22-19-13-7-10-16-9-4-5-12-18(16)19/h4-14H,3H2,1-2H3,(H2,21,22) checkY
  • Key:BFNCJMURTMZBTE-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Aptiganel (Cerestat; CNS-1102) is an unsuccessful drug candidate which acts as a noncompetitive NMDA antagonist, and that was under development by Cambridge Neuroscience, Inc as a treatment for stroke.[1] It has neuroprotective effects and was researched for potential use in the treatment of stroke,[2] but despite positive results in animal studies,[3] human trials showed limited efficacy,[4] as well as undesirable side effects such as sedation and hallucinations,[5][6] and clinical development was ultimately not continued.[7]

The drug's failure led to the collapse of Cambridge Neuroscience in 1998[8] and its eventual sale to CeNeS Pharmaceuticals in 2000.[9]

Other guanidine substances that the company had been bowling on was Cns-1145 & CNS1237.

Synthesis

Aptiganel synthesis:[10][11]

1-Naphthylamine is reacted with cyanogen bromide to give 2. Treatment of this intermediate with 3-ethyl-N-methylaniline leads to addition to the cyano group and formation of the corresponding diaryl guanidine, aptiganel, 3.

See also

  • Ditolylguanidine
  • CNS1237 shares predominantly most of the same structural entities.

References

  1. ↑ Reddy NL, Hu LY, Cotter RE, Fischer JB, Wong WJ, McBurney RN, et al. (January 1994). "Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist". Journal of Medicinal Chemistry. 37 (2): 260–7. doi:10.1021/jm00028a009. PMID 8295213.
  2. ↑ Muir KW, Grosset DG, Gamzu E, Lees KR (July 1994). "Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers". British Journal of Clinical Pharmacology. 38 (1): 33–8. doi:10.1111/j.1365-2125.1994.tb04318.x. PMC 1364834. PMID 7946934.
  3. ↑ Schäbitz WR, Li F, Fisher M (July 2000). "The N-methyl-D-aspartate antagonist CNS 1102 protects cerebral gray and white matter from ischemic injury following temporary focal ischemia in rats". Stroke. 31 (7): 1709–14. doi:10.1161/01.str.31.7.1709. PMID 10884477.
  4. ↑ Albers GW, Goldstein LB, Hall D, Lesko LM (December 2001). "Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial". JAMA. 286 (21): 2673–82. doi:10.1001/jama.286.21.2673. PMID 11730442.
  5. ↑ Muir KW, Grosset DG, Lees KR (August 1997). "Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers". Clinical Neuropharmacology. 20 (4): 311–21. doi:10.1097/00002826-199708000-00003. PMID 9260729.
  6. ↑ Lees KR (November 1997). "Cerestat and other NMDA antagonists in ischemic stroke". Neurology. 49 (5 Suppl 4): S66-9. doi:10.1212/wnl.49.5_suppl_4.s66. PMID 9371155. S2CID 45771202.
  7. ↑ Hoyte L, Barber PA, Buchan AM, Hill MD (March 2004). "The rise and fall of NMDA antagonists for ischemic stroke". Current Molecular Medicine. 4 (2): 131–6. doi:10.2174/1566524043479248. PMID 15032709.
  8. ↑ Staff, Boston Business Journal. May 7, 1998. CNSI appoints new president, CEO
  9. ↑ Staff, ICIS. 23 May 2000 CeNeS to buy US neuroscience firm CNSI for $44m
  10. ↑ Reddy NL, Hu LY, Cotter RE, Fischer JB, Wong WJ, McBurney RN, et al. (January 1994). "Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist". Journal of Medicinal Chemistry. 37 (2): 260–7. doi:10.1021/jm00028a009. PMID 8295213.
  11. ↑ WO 9112797, Weber, Eckard & Keana, John F. W., "Tri- and tetra-substituted guanidines and their use as excitatory amino acid antagonists", published 1991-09-05, assigned to University of Oregon and Oregon Health Sciences University; E. Weber, J. F. W. Keana, U.S. Patent 5,262,568 (1993 to State of Oregon)
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