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Bioorg Med Chem Lett. 2012 Dec 1;22(23):7106-9. doi: 10.1016/j.bmcl.2012.09.080. Epub 2012 Sep 29.

Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate.

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1
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Vic. 3052, Australia.

Abstract

Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC(50) values.

PMID:
23084278
PMCID:
PMC3664202
DOI:
10.1016/j.bmcl.2012.09.080
[Indexed for MEDLINE]
Free PMC Article
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