Aptiganel Explained

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

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.

Notes and References

1. Reddy NL, Hu LY, Cotter RE, Fischer JB, Wong WJ, McBurney RN, Weber E, Holmes DL, Wong ST, Prasad R . 6 . 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 . January 1994 . 8295213 . 10.1021/jm00028a009 .
2. Muir KW, Grosset DG, Gamzu E, Lees KR . Pharmacological effects of the non-competitive NMDA antagonist CNS 1102 in normal volunteers . British Journal of Clinical Pharmacology . 38 . 1 . 33–8 . July 1994 . 7946934 . 1364834 . 10.1111/j.1365-2125.1994.tb04318.x .
3. Schäbitz WR, Li F, Fisher M . 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 . July 2000 . 10884477 . 10.1161/01.str.31.7.1709 . free .
4. Albers GW, Goldstein LB, Hall D, Lesko LM . Aptiganel hydrochloride in acute ischemic stroke: a randomized controlled trial . JAMA . 286 . 21 . 2673–82 . December 2001 . 11730442 . 10.1001/jama.286.21.2673 .
5. Muir KW, Grosset DG, Lees KR . Effects of prolonged infusions of the NMDA antagonist aptiganel hydrochloride (CNS 1102) in normal volunteers . Clinical Neuropharmacology . 20 . 4 . 311–21 . August 1997 . 9260729 . 10.1097/00002826-199708000-00003 .
6. Lees KR . Cerestat and other NMDA antagonists in ischemic stroke . Neurology . 49 . 5 Suppl 4 . S66-9 . November 1997 . 9371155 . 10.1212/wnl.49.5_suppl_4.s66 . 45771202 .
7. Hoyte L, Barber PA, Buchan AM, Hill MD . The rise and fall of NMDA antagonists for ischemic stroke . Current Molecular Medicine . 4 . 2 . 131–6 . March 2004 . 15032709 . 10.2174/1566524043479248 .
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