The Discovery of Piragliatin, a Glucokinase Activator - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 67

reaction of the chiral ketal 34 to the bicyclic intermediate 35; (b) opening of the
cyclopropane of 35 to alkyl iodide 36 using iodotrimethylsilane; and (c) the
diastereoselective alkylation of chiral amide 37 to yield the critical phenylaceta-
mide 38. Thus, both the (R,S)- (32)and(R,R)- (33) diastereomers, corresponding
to the C3-keto metabolites of 27 20 (Scheme 3.1), were available. In vitro and in
vivo evaluation and comparison of both diastereomers (Figures 3.16 and 3.17)

O O

R

S

N N

R R

N

N

O

O

S

S N

N

O O O O

Cl

Cl

32
SC 1.5 -5.6

33
(Piragliatin)
SC 1.5 -0.18

M
hERG IC 20 -10 µ M

µ

M
hERG IC 20 -6 µ M
TDI - 3A4 - 12%

µ

Figure 3.16

In vitro potency of C3 ketone metabolites of 27.

200

180

160

140

120

100

80

60

Vehicle
33
32

40

20

0

-60 0 60 120 180 240 300 360

Time (min.)

Figure 3.17 In vivo potency of 32 and 33, C3 ketone metabolites of 27, in diabetic

diet-induced obese mice (n ¼ 8/group). C57Bl/6J mice were fed a high-fat
diet for 16.7 weeks and fasted for 2 h prior to oral administration of
vehicle or test compound (15mg kg 1 ). Animals were fasted for the
duration of the study.