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Your search keyword '"Shuto, Daisuke"' showing total 2 results
Start Over Author "Shuto, Daisuke" Topic aspartic acid endopeptidases
2 results on '"Shuto, Daisuke"'

1. Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability.

Author

Kimura T, Shuto D, Hamada Y, Igawa N, Kasai S, Liu P, Hidaka K, Hamada T, Hayashi Y, and Kiso Y

Subjects
Amyloid Precursor Protein Secretases, Drug Stability, Endopeptidases, Models, Molecular, Oligopeptides chemistry, Protease Inhibitors chemistry, Aspartic Acid Endopeptidases antagonists & inhibitors, Oligopeptides chemical synthesis, Oligopeptides pharmacology, Protease Inhibitors chemical synthesis, Protease Inhibitors pharmacology
Abstract

Recently, we reported potent and small-sized BACE1 inhibitors KMI-358 and KMI-370 in which the Glu residue is replaced by a beta-N-oxalyl-DAP (l-alpha,beta-diaminopropionyl) residue at the P(4) position. The beta-N-oxalyl-DAP group is important for enhancing BACE1 inhibitory activity, but these inhibitors isomerized to alpha-N-oxalyl-DAP derivatives in solvents. Hence, we used a tetrazole moiety as a bioisostere of the free carboxylic acid of the oxalyl group. KMI-420 and KMI-429, containing a tetrazole ring, showed improved stability and potent enzyme inhibitory activity.

Published
2005
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2. KMI-358 and KMI-370, highly potent and small-sized BACE1 inhibitors containing phenylnorstatine.

Author

Kimura T, Shuto D, Kasai S, Liu P, Hidaka K, Hamada T, Hayashi Y, Hattori C, Asai M, Kitazume S, Saido TC, Ishiura S, and Kiso Y

Subjects
Amyloid Precursor Protein Secretases, Aspartic Acid Endopeptidases metabolism, Cell Line, Dose-Response Relationship, Drug, Endopeptidases, Humans, Phenylbutyrates metabolism, Protease Inhibitors metabolism, Aspartic Acid Endopeptidases antagonists & inhibitors, Phenylbutyrates chemistry, Protease Inhibitors chemistry
Abstract

Recently, we reported a novel substrate-based octapeptide BACE1 inhibitor KMI-008 containing hydroxymethylcarbonyl (HMC) isostere as a transition-state mimic. Using KMI-008 as a lead compound, a small-sized and highly potent BACE1 inhibitor KMI-370 (IC(50)=3.4 nM) was designed and synthesized.

Published
2004
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