Abstract
We previously reported a potent calpain inhibitor 1 (SJA6017, N-(4-fluorophenyl)-l-valyl-l-leucinal), which displayed relatively low oral bioavailability (BA). Replacing the metabolically labile aldehyde moiety of 1with more chemically stable warheads, such as a cyclic hemiacetal, hydrazone, and alpha-ketoamide, provided the inhibitors with improved in vitro metabolic stability. Cyclic hemiacetal 2 was the most stable of these compounds. The optimization of 2 led to hemiacetal 8 (SNJ-1715) which exhibited high potency, good aqueous solubility, excellent oral BA, and prolonged plasma half-life in rats. Furthermore, 8 showed neuroprotective efficacy via oral administration in a rat retinal ischemia model.
MeSH terms
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Administration, Oral
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Animals
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Calpain / antagonists & inhibitors*
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Cell Line
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Dipeptides / chemical synthesis*
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Dipeptides / pharmacokinetics
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Dipeptides / pharmacology
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Drug Stability
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Half-Life
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Humans
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Ischemia / pathology
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Ischemia / prevention & control
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Male
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Neuroprotective Agents / chemical synthesis*
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / pharmacology
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Rats
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Rats, Sprague-Dawley
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Reperfusion Injury / pathology
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Reperfusion Injury / prevention & control
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Retinal Diseases / pathology
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Retinal Diseases / prevention & control
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Retinal Ganglion Cells / drug effects
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Retinal Ganglion Cells / pathology
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
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Thiourea / analogs & derivatives*
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Thiourea / chemical synthesis
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Thiourea / pharmacokinetics
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Thiourea / pharmacology
Substances
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Dipeptides
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N-(4-fluorophenylsulfonyl)-L-valyl-L-leucinal
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Neuroprotective Agents
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SNJ 1715
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Calpain
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Thiourea