Identification of activating enzymes of a novel FBP ase inhibitor prodrug, CS ‐917
Abstract CS ‐917 ( MB 06322) is a selective small compound inhibitor of fructose 1,6‐bisphosphatase ( FBP ase), which is expected to be a novel drug for the treatment of type 2 diabetes by inhibiting gluconeogenesis. CS ‐917 is a bisamidate prodrug and activation of CS ‐917 requires a two‐step enzym...
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Published in | Pharmacology research & perspectives Vol. 3; no. 3 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Bognor Regis
John Wiley & Sons, Inc
01.06.2015
|
Subjects | |
Online Access | Get full text |
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Summary: | Abstract
CS
‐917 (
MB
06322) is a selective small compound inhibitor of fructose 1,6‐bisphosphatase (
FBP
ase), which is expected to be a novel drug for the treatment of type 2 diabetes by inhibiting gluconeogenesis.
CS
‐917 is a bisamidate prodrug and activation of
CS
‐917 requires a two‐step enzyme catalyzed reaction. The first‐step enzyme, esterase, catalyzes the conversion of
CS
‐917 into the intermediate form (R‐134450) and the second‐step enzyme, phosphoramidase, catalyzes the conversion of R‐134450 into the active form (R‐125338). In this study, we biochemically purified the
CS
‐917 esterase activity in monkey small intestine and liver. We identified cathepsin A (
CTSA
) and elastase 3B (
ELA
3B) as
CS
‐917 esterases in the small intestine by mass spectrometry, whereas we found
CTSA
and carboxylesterase 1 (
CES
1) in monkey liver. We also purified R‐134450 phosphoramidase activity in monkey liver and identified sphingomyelin phosphodiesterase, acid‐like 3A (
SMPADL
3A), as an R‐134450 phosphoramidase, which has not been reported to have any enzyme activity. Recombinant human
CTSA
,
ELA
3B, and
CES
1 showed
CS
‐917 esterase activity and recombinant human
SMPDL
3A showed R‐134450 phosphoramidase activity, which confirmed the identification of those enzymes. Identification of metabolic enzymes responsible for the activation process is the requisite first step to understanding the activation process, pharmacodynamics and pharmacokinetics of
CS
‐917 at the molecular level. This is the first identification of a phosphoramidase other than histidine triad nucleotide‐binding protein (
HINT
) family enzymes and
SMPDL
3A might generally contribute to activation of the other bisamidate prodrugs. |
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ISSN: | 2052-1707 2052-1707 |
DOI: | 10.1002/prp2.138 |