Chemistry:Enecadin
Enecadin (NS-7) was an investigational new drug developed as a neuroprotectant for use following cerebral infarction (stroke). It was originally discovered by Nippon Shinyaku and later out-licensed to Schering in 1999.[1]
Enecadin exerts its neuroprotective effects by blocking voltage-gated sodium and calcium channels, which play key roles in excitotoxicity during ischemic injury. By limiting pathological ion influx, the compound was shown to preserve neuronal integrity in experimental models of stroke, spinal cord injury, and retinal ischemia.[2][3][4]
The drug advanced to Phase II clinical trials for acute ischemic stroke, but development was discontinued after the trial was terminated.[5]
Synthesis
Patent:[6]
A Claisen-Schmidt reaction between p-fluoroacetophenone [403-42-9] (1) and diethyl carbonate [105-58-8] (2) gives ethyl 3-(4-fluorophenyl)-3-oxopropanoate [1999-00-4] (3). Treatment with acetamidine hydrochloride [124-42-5] (4) leads to the formation of 4-(4-fluorophenyl)-6-hydroxy-2-methylpyrimidine [178430-09-6] (5). Halogenation with phosphoryl chloride led to 4-chloro-6-(4-fluorophenyl)-2-methylpyrimidine [178430-13-2] (6). Williamson ether synthesis with 5-piperidino-1-pentanol [2937-83-9] (7) completed the synthesis of Enecadin (8).
See also
- p-fluoroacetophenone finds dual use in the synthesis of Flazalone.
References
- ↑ "NS-7 (Nippon Shinyaku)". IDrugs: The Investigational Drugs Journal 3 (4): 460–465. April 2000. PMID 16100702.
- ↑ "Medicinal Chemistry of Neuronal Voltage-Gated Sodium Channel Blockers". Journal of Medicinal Chemistry 44 (2): 115–137. 1 January 2001. doi:10.1021/jm000155h. PMID 11170622.
- ↑ "Blockade of voltage-sensitive sodium channels by NS-7, a novel neuroprotective compound, in the rat brain". Naunyn-schmiedeberg's Archives of Pharmacology 355 (5): 601–608. May 1997. doi:10.1007/pl00004990. PMID 9151299.
- ↑ "Neuroprotective effect of NS-7, a novel Na+ and Ca2+ channel blocker, in a focal ischemic model in the rat". Brain Research 969 (1–2): 168–174. April 2003. doi:10.1016/s0006-8993(03)02296-0. PMID 12676377.
- ↑ Clinical trial number NCT00331721 for "Tolerability of Enecadin (INN) in Acute Ischemic Stroke Trial - TEST" at ClinicalTrials.gov
- ↑ Chokai S, Ukai Y, Aoki T, Ideguchi K, "Heterocyclic derivative and medicine", WO patent 1996007641, published 1996-03-14, assigned to Nippon Shinyaku Co., Ltd.
 |  |
