Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives

Ki Yong Lee; Kwang Seob Lee; Changbae Jin; Yong Sup Lee

doi:10.1016/j.ejmech.2008.02.023

Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives

Ki Yong Lee, Kwang Seob Lee, Changbae Jin, Yong Sup Lee

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

Abstract

Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of μ-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic μ-calpain inhibitor, MDL 28,170, and their μ-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited μ-calpain with an IC₅₀ value of 2.81 ± 1.26 μM, which is ca. 40-fold less than that of MDL 28,170.

Original language	English
Pages (from-to)	1331-1334
Number of pages	4
Journal	European Journal of Medicinal Chemistry
Volume	44
Issue number	3
DOIs	https://doi.org/10.1016/j.ejmech.2008.02.023
Publication status	Published - Mar 2009

Bibliographical note

Funding Information:
This research was supported by the Mid-Term Technological Development Project funded by the Korean Ministry of Commerce, Industry and Energy (grant no. 10027898-2007-22).

Keywords

6-Pyridone
Calpain inhibitor
Conformational restriction
Stroke

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10.1016/j.ejmech.2008.02.023

Cite this

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title = "Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives",

abstract = "Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of μ-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic μ-calpain inhibitor, MDL 28,170, and their μ-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited μ-calpain with an IC50 value of 2.81 ± 1.26 μM, which is ca. 40-fold less than that of MDL 28,170.",

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author = "Lee, {Ki Yong} and {Seob Lee}, Kwang and Changbae Jin and Lee, {Yong Sup}",

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AU - Seob Lee, Kwang

AU - Jin, Changbae

AU - Lee, Yong Sup

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AB - Excessive calpain activation contributes to serious cellular damage in many pathological conditions. The involvement of μ-calpain in neurological disorders such as, stroke and Alzheimer's disease has attracted considerable interest in the use of calpain inhibitors as therapeutic agents. 6-Pyridone 2-carboxamides derived from ketoamides were synthesized as conformationally constrained structures resembling the well known peptidic μ-calpain inhibitor, MDL 28,170, and their μ-calpain inhibitory activities were evaluated. Of the compounds synthesized, compound 2a, which has a primary amide at warhead region of the inhibitor most potently inhibited μ-calpain with an IC50 value of 2.81 ± 1.26 μM, which is ca. 40-fold less than that of MDL 28,170.

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KW - Calpain inhibitor

KW - Conformational restriction

KW - Stroke

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Design and synthesis of calpain inhibitory 6-pyridone 2-carboxamide derivatives

Abstract

Bibliographical note

Keywords

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