Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives as neuronal voltage-gated sodium channel blockers

• Published in: Bioorganic & medicinal chemistry letters 2009-10, Vol.19 (19), p.5644-5647
• Main Authors: Ma, Xiang, Poon, Thong-Yuen, Wong, Peter Tsun Hon, Chui, Wai-Keung
• Format: Article
• Language: English
• Subjects: 2,4-Diamino-1,3,5-triazines; Animals; Anticonvulsants - chemical synthesis; Anticonvulsants - chemistry; Anticonvulsants - pharmacology; Anticonvulsants. Antiepileptics. Antiparkinson agents; Antiepilepsy; Biological and medical sciences; Cattle; Central Nervous System Diseases - drug therapy; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Sodium channel blockers; Sodium Channel Blockers - chemical synthesis; Sodium Channel Blockers - chemistry; Sodium Channel Blockers - pharmacology; Sodium Channels - chemistry; Sodium Channels - metabolism; Tetrahydrofolate Dehydrogenase - metabolism; Triazines - chemical synthesis; Triazines - chemistry; Triazines - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.08.052

A series of 2,4-diamino-1,3,5-triazine derivatives was synthesized and examined as neuronal voltage-gated sodium channel blockers. Compound 4c has shown significant in vitro neuronal sodium channel binding activity with no antifolate effect. Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-triazine derivatives were synthesized and investigated for their neuronal sodium channels binding activity. 5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines ( 4a– 4j) were found to have the best neuronal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a– 4j blocked the sodium channels with IC 50 values ranged from 4.0 to 14.7 μM. The result from this study showed that analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium channels blockers for managing central nervous system related disorders.