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| Dual action NEP-DPPIV inhibitors as a concept for the treatment of type II diabetes | |
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A significant, rapidly growing fraction of the human population is
affected by type 2 diabetes, a disease characterized by elevated
blood glucose levels and relative insufficiency of insulin. The
activity of two potent stimulators of insulin secretion, GLP-1 and
GIP, is rapidly abolished by the serine peptidase dipeptidyl
peptidase IV (DPP-IV). In vivo administration of synthetic
inhibitors of DPP-IV prevents N-terminal degradation of GLP-1 and
GIP, resulting in higher plasma concentrations of these hormones,
increased insulin secretion and improved glucose tolerance. Several
companies are currently developing DPP-IV inhibitors for diabetes.
Within the kidney, GLP-1 clearance is primarily due to neutral
endopoeptidase (NEP). Prolonged GLP-1 stability has been shown by
a combined inhibition of NEP and DPP-IV in pigs. Deacon and
co-workers have shown that treatment of diabetic rats with a
combination of a DPP-IV and a NEP inhibitor results in
glucose-lowering effects superior to those observed using only a
DPP-IV inhibitor.
The rationally designed dual inhibition of two molecular targets
involved in a disease is best exemplified by the drug Omapatrilat.
This compound is used in the treatment of hypertension and chronic
heart failure as a result of the synergistic effects of the
component drugs on polypeptide levels. It simultaneously inhibits
two zinc-containing endopeptidases: angiotensin converting enzyme
(ACE) and NEP.
Based on the structural knowledge of NEP and DPP-IV, in particular
the understanding of their sub-site specificity, a dual inhibition
concept was followed. Inhibitors of DPP-IV can be linked via their
terminal unprimed substituent with NEP inhibitors either with their
terminal unprimed residue, their two-primed residue or the
C-terminal moiety.
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