Chemistry Reference
In-Depth Information
O
HO
H
N
H
N
N
N
O
S
O
S
S
S
O
O
O
O
N
N
S
O
S
N
O
O
NH
2
9a
O
S
S
O
O
Figure 3.12
Primary metabolite profile of 9a.
O
H
N
H
N
N
N
N
N
H
O
S
O
S
O
S
O
S
S
S
O
O
O
O
O
O
9
H
N
NH
2
O
S
S
O
O
10
Figure 3.13
Mechanism of thiourea formation.
(SC
1.5
ΒΌ
45 mM) as structural probes for 9a and its key metabolite. In a five-day
rat toxicology study, either a dose of 250mg kg
1
of 9b or doses from 10 to
300mg kg
1
of 10 caused hepatic lipidosis in rats in the absence of glucose
lowering. These findings strongly supported the hypothesis that the thiourea
metabolite formed via oxidative thiazole ring opening was the primary cause
for the observed hepatic lipidosis associated with 9a, rather than the GK
activity of 9a, and set the stage for the discovery of a safer compound incapable
of this transformation.
18
As a first step, several substituted thiazole analogs (Table 3.2) of 9a that were
either monosubstituted (compounds 19-25) or the benzothiazole 26 were
investigated for their propensity to form the thiourea metabolite in human liver
microsomes. These studies demonstrated a marked reduction in their pro-
pensity to undergo oxidation of the thiazole ring, particularly when the thiazole
substituent was an electron-withdrawing group, such as chloro or nitro.
Search WWH ::
Custom Search