Enecadin

Enecadin
Clinical data
Other names	NS-7
Identifiers
	IUPAC name 4-(4-Fluorophenyl)-2-methyl-6-(5-piperidin-1-ylpentoxy)pyrimidine;
CAS Number	259525-01-4 178429-67-9;
PubChem CID	6433114;
DrugBank	DB13032;
ChemSpider	4938302;
UNII	VR034VW8OG;
ChEMBL	ChEMBL29404;
CompTox Dashboard (EPA)	DTXSID30948865 ;
Chemical and physical data
Formula	C21H28FN3O
Molar mass	357.473 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=NC(=CC(=N1)OCCCCCN2CCCCC2)C3=CC=C(C=C3)F;
	InChI InChI=1S/C21H28FN3O/c1-17-23-20(18-8-10-19(22)11-9-18)16-21(24-17)26-15-7-3-6-14-25-12-4-2-5-13-25/h8-11,16H,2-7,12-15H2,1H3; Key:SZSHJTJCJOWMHM-UHFFFAOYSA-N;

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).

References

^ Small DL (April 2000). "NS-7 (Nippon Shinyaku)". IDrugs: The Investigational Drugs Journal. 3 (4): 460–465. PMID 16100702.
^ Anger T, Madge DJ, Mulla M, Riddall D (1 January 2001). "Medicinal Chemistry of Neuronal Voltage-Gated Sodium Channel Blockers". Journal of Medicinal Chemistry. 44 (2): 115–137. doi:10.1021/jm000155h. PMID 11170622.
^ Shimidzu T, Itoh Y, Tatsumi S, Hayashi S, Ukai Y, Yoshikuni Y, et al. (May 1997). "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. doi:10.1007/pl00004990. PMID 9151299.
^ Katsumata T, Muramatsu H, Nakamura H, Nishiyama Y, Aoki Y, Katayama Y (April 2003). "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. 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
^ WO 1996007641, Chokai S, Ukai Y, Aoki T, Ideguchi K, "Heterocyclic derivative and medicine", published 1996-03-14, assigned to Nippon Shinyaku Co., Ltd.

[Small_2000-1] Small DL (April 2000). "NS-7 (Nippon Shinyaku)". IDrugs: The Investigational Drugs Journal. 3 (4): 460–465. PMID 16100702.

[2] Anger T, Madge DJ, Mulla M, Riddall D (1 January 2001). "Medicinal Chemistry of Neuronal Voltage-Gated Sodium Channel Blockers". Journal of Medicinal Chemistry. 44 (2): 115–137. doi:10.1021/jm000155h. PMID 11170622.

[Shimidzu_1997-3] Shimidzu T, Itoh Y, Tatsumi S, Hayashi S, Ukai Y, Yoshikuni Y, et al. (May 1997). "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. doi:10.1007/pl00004990. PMID 9151299.

[Katsumata_2003-4] Katsumata T, Muramatsu H, Nakamura H, Nishiyama Y, Aoki Y, Katayama Y (April 2003). "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. doi:10.1016/s0006-8993(03)02296-0. PMID 12676377.

[5] Clinical trial number NCT00331721 for "Tolerability of Enecadin (INN) in Acute Ischemic Stroke Trial - TEST" at ClinicalTrials.gov

[6] WO 1996007641, Chokai S, Ukai Y, Aoki T, Ideguchi K, "Heterocyclic derivative and medicine", published 1996-03-14, assigned to Nippon Shinyaku Co., Ltd.

[1]

[2]

[3]

[4]

[5]

[6]

Synthesis

See also

References