Dipeptidyl peptidase-4 is a target in diabetes therapy. The impact of
mono-, bi- and tricyclic derivatives of imidazole, thiazole, pyridine,
pyran, pyrimidine and morpholine on the activity of recombinant
human dipeptidyl peptidase-4 was evaluated by spectrophotometric
method in vitro compared with sitagliptin and diprotin A as reference
inhibitors, clarifying the mechanism of inhibition and structureactivity
relationship of the most effective inhibitors. Derivatives of
benzimidazol-2-imine, bis(benzimidazol-2-yl)amine, 6-
(phenylcarbonyl)-[1,3]thiazolo[3,2-a]benzimidazol-3-one,
benzo[4,5]thieno[2,3-d]pyrimidin-4-amine and -phthalimide inhibited
dipeptidyl peptidase-4 with IC50 < 200 μM.
2-(2-(3-Chlorobenzyl)-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-
d]pyrimidin-4-yl)isoindoline-1,3-dione was about two times less
effective than diprotin A, with noncompetitive type of inhibition,
what might be explained by absence of interactions with Glu205,
Glu206 and S1 pocket of dipeptidyl peptidase-4....
1-Propyl-N-(1-propyl-1H-benzimidazol-2-yl)-1H-benzimidazol-2-
amine and 1-methyl-N-(1-propyl-1H-benzimidazol-2-yl)-1Hbenzimidazol-
2-amine showed about three and one and a half times
higher effectivenes, respectively, while 1-ethyl-N-(1-propyl-1Hbenzimidazol-
2-yl)-1H-benzimidazol-2-amine was about three times
less effective than diprotin A. The S2 extensive subsite of dipeptidyl
peptidase-4 participates in interactions with these structures, what
presumably contributes to their higher activity.
Besides dipeptidyl peptidase-4, 2-[2-imino-5-nitro-3-(2-oxo-2-
phenylethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-phenylethanone
and 2-(4-fluorobenzylidene)-6-(phenylcarbonyl)[1,3]thiazolo[3,2-
a]benzimidazol-3(2H)-one inhibited xanthine oxidase in vitro with
IC50 < 150 μM, in spectrophotometric assay. Potential pronounced
cardiovascular protective effects of dual dipeptidyl peptidase-4 and
xanthine oxidase inhibitors were considered.
Effective benzo[4,5]thieno[2,3-d]pyrimidine derivatives and dual
inhibitors were not cytotoxic to a greater extent at concentrations
below 250 μM, assessed on Caco-2 cells by MTT assay.
The significance and mechanisms of multiple biochemical effects of
dipeptidyl peptidase-4 inhibition and pleiotropis effects of existing
and new, including those found in this dissertation, inhibitors were
considered in order to assess possible broadening of range of
indications, pointing to protective effects in cardiovascular and renal
pathology by affecting mediators of inflammation, oxidative stress,
fibrosis and apoptosis, to beneficial effects on postischemic
angiogenesis mediated by prevention of stromal cell-derived factor-1
cleavage, and to pulmonary hypertension as possible indication of
inhibitors effective in irreversible phase of remodeling.
