Abstract
To investigate the molecular design of drugs that have good penetration into the retina from anterior segment of the eye via ocular instillation, we optimized the length of methoxyethylene glycol chain (mEG) in the P3 region of an oral bioavailable calpain inhibitor SNJ-1945 (2) as a model compound. Modulation of the mEG length led to the optimal balance between hydrophilicity and lipophilicity and provided the compound with higher retinal exposure via ocular instillation. Incorporation of a mEG moiety would be a useful and convenient approach to attain high intraocular penetration.
MeSH terms
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Administration, Oral
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Animals
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Calpain / antagonists & inhibitors*
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Carbamates / blood
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Carbamates / chemical synthesis*
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Carbamates / chemistry
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Carbamates / pharmacology*
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Drug Design*
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Enzyme Inhibitors / blood
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics*
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Humans
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Injections, Intravenous
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Macaca fascicularis
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Molecular Structure
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Rabbits
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Retina / drug effects
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Retina / metabolism*
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Structure-Activity Relationship
Substances
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((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester
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Carbamates
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Enzyme Inhibitors
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Calpain