The dammarane triterpenoid (20
S
,24
R
)-epoxy-dammarane-3
β
,12
β
,25-triol obtained from
Cyclocarya paliurus
in our previous study showed inhibitory activity on
α
-glucosidase in vitro with an inhibitory ratio of 32.2% at the concentration of 200 μM. In order to reveal the structure-activity relationships (SARs) and get more active compounds, 42 derivatives of (20
S
,24
R
)-epoxy-dammarane-3
β
,12
β
,25-triol were synthesized by chemical modification on the hydroxyls (C-3 and C-12), rings A and E, and assayed for their
α
-glucosidase and PTP1B inhibitory activities. Two compounds (
8
,
26
) increased activity against
α
-glucosidase, and four compounds (
8
,
15
,
26
,
42
) significantly inhibited PTP1B. It was noted that compounds
8
and
26
could inhibit both
α
-glucosidase and PTP1B as dual-target inhibitors with IC
50
values of 489.8, 467.7 μM (
α
-glucosidase) and 319.7, 269.1 μM (PTP1B). Compound
26
was revealed to be a mix-type inhibitor on
α
-glucosidase and a noncompetitive-type inhibitor on PTP1B based on enzyme kinetic study. Furthermore, compound
42
could selectively inhibited PTP1B as a mix-type inhibitor with IC
50
value of 134.9 μM, which was 2.5-fold higher than the positive control, suramin sodium (IC
50
339.0 μM), but not inhibit
α
-glucosidase.