AL-34662
AL-34662 is an indazole derivative drug that is being developed for the treatment of glaucoma. It acts as a selective 5-HT2A receptor agonist, the same target as that of psychedelic drugs like psilocin, but unlike these drugs, AL-34662 was designed specifically as a peripherally selective drug, which does not cross the blood–brain barrier. This means that AL-34662 can exploit a useful side effect of the hallucinogenic 5-HT2A agonists, namely reduction in intra-ocular pressure and hence relief from the symptoms of glaucoma, but without causing the hallucinogenic effects that make centrally active 5-HT2A agonists unsuitable for clinical use.[1] In animal studies, AL-34662 has been shown to be potent and effective in the treatment of symptoms of glaucoma, with minimal side effects.[2]
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Formula | C10H13N3O |
Molar mass | 191.234 g·mol−1 |
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Melting point | 170 to 172 °C (338 to 342 °F) |
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Peripherally acting 5-HT2A agonists have been a rich field of research in recent years, with potential glaucoma treatments being the main proposed application for 5-HT2A agonists at present, as centrally acting agonists for this receptor tend to be hallucinogenic and thus have little medical use. While many novel, potent and selective 5-HT2A agonists have been developed for this application,[3] [4] [5][6][7][8][9][10] retaining peripheral selectivity can be a problem, and several of the more lipophilic compounds closely related to AL-34662 such as those shown below, did cross the blood–brain barrier and produced hallucinogen-appropriate responding in animals.[11]
References
- Sharif NA, Kelly CR, Crider JY, Davis TL (December 2006). "Serotonin-2 (5-HT2) receptor-mediated signal transduction in human ciliary muscle cells: role in ocular hypotension". Journal of Ocular Pharmacology and Therapeutics. 22 (6): 389–401. doi:10.1089/jop.2006.22.389. PMID 17238805.
- Sharif NA, McLaughlin MA, Kelly CR (February 2007). "AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist". Journal of Ocular Pharmacology and Therapeutics. 23 (1): 1–13. doi:10.1089/jop.2006.0093. PMID 17341144.
- May JA, Chen HH, Rusinko A, Lynch VM, Sharif NA, McLaughlin MA (September 2003). "A novel and selective 5-HT2 receptor agonist with ocular hypotensive activity: (S)-(+)-1-(2-aminopropyl)-8,9-dihydropyrano[3,2-e]indole". Journal of Medicinal Chemistry. 46 (19): 4188–95. doi:10.1021/jm030205t. PMID 12954071.
- US granted 6806285, May JA, Zinke PW, "6-Hydroxyl indole derivatives for treating glaucoma", issued 19 October 2004, assigned to Alcon Inc.
- US granted 6956036, May JA, Feng X, Dantanarayana AP, "6-Hydroxy-indazole derivatives for treating glaucoma", issued 18 October 2005, assigned to Alcon Inc.
- US application 6960608, May JA, Dantanarayana AP, "Fused indazoles and indoles and their use for the treatment of glaucoma", assigned to Alcon Inc.
- US granted 7005443, May JA, Feng Z, "5-Hydroxy indazole derivatives for treating glaucoma", issued 28 February 2006, assigned to Alcon Inc.
- US granted 7208512, Feng Z, Mark R. Hellberg, "Benzodifuranimidazoline and benzofuranimidazoline derivatives and their use for the treatment of glaucoma", assigned to Alcon Inc.
- US granted 7268131, Dantanarayana AP, May JA, "Substituted (1,4)oxazino(2,3-g)indazoles for the treatment of glaucoma"
- US granted 7338972, Dantanarayana AP, May JA, "Substituted 1-alkylamino-1H-indazoles for the treatment of glaucoma", assigned to Alcon Inc.
- May JA, Dantanarayana AP, Zinke PW, McLaughlin MA, Sharif NA (January 2006). "1-((S)-2-aminopropyl)-1H-indazol-6-ol: a potent peripherally acting 5-HT2 receptor agonist with ocular hypotensive activity". Journal of Medicinal Chemistry. 49 (1): 318–28. doi:10.1021/jm050663x. PMID 16392816.