Exploration of Orally Available Calpain Inhibitors 2: Peptidyl Hemiacetal Derivatives.
From: Senju Pharmaceutical Company, Ltd., 1-5-4 Murotani, Nishi-ku, Kobe, Hyogo 651-2241, Japan. shirasaki@senju.co.jp
Journal of medicinal chemistry
- Publish Date: Jun 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 13
- Pages: 3926-32
- Medium: Print
- Language: English
- Citation (JAMA): Shirasaki Yoshihisa, Nakamura Masayuki, Yamaguchi Masazumi, et al. Exploration of Orally Available Calpain Inhibitors 2: Peptidyl Hemiacetal Derivatives.. J. Med. Chem. Jun 2006;49:3926-32
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 Headings (Keywords): Administration, Oral, Animals, Calpain, Cell Line, Dipeptides, Drug Stability, Half-Life, Humans, Ischemia, Male, Neuroprotective Agents, Rats, Rats, Sprague-Dawley, Reperfusion Injury, Retinal Diseases, Retinal Ganglion Cells, Solubility, Stereoisomerism, Structure-Activity Relationship, Thiourea
Check for Full Text / PubMed Unique Identifier (PMID): 16789748
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