Chemistry Reference
In-Depth Information
H-Donor
H-Donor
H-Acceptor
H-Acceptor
H
N
H
N
N
O
O
O
N
Cl
n
Cl
H
H
Cl
Cl
H-Bond
1
I
Figure 3.9
Intramolecular H-bond and cis-amide characteristics of 1 and the resulting
2-amino heteroaromatic ring hypothesis.
Table 3.1 Key aromatic ring SAR findings related to 9a.
R
3
R
3
N
N
N
N
O
O
S
S
O
O
O
O
Cl
Compound R
3
SC
1.5
(mM) Compound R
3
SC
1.5
(mM)
9
thiazolyl
0.34
14
thiazolyl
0.12
10
2-pyridyl
1.21
15
2-pyridyl
0.083
11
2-pyrazinyl
1.78
16
2-pyrazinyl
0.18
12
2-quinolyl
1.38
17
2-quinolyl
0.12
13
3-pyrimidinyl
1.74
18
3-pyrimidinyl
0.19
summarized in Table 3.2 (compounds 19-26). In general, the SAR at R
1
and R
2
of phenylacetamidothiazoles was parallel to that of the N-acylureas. Similar to
N-acylureas, the (R)-stereoisomer 9a potently activated GK (SC
1.5
ΒΌ
0.35 mM),
while the corresponding (S)-isomer 9b did not activate GK at up to 10 mM.
The structural elements required in a phenylacetamide-based GK activator
provided by SAR studies can be summarized as follows: (i) an electron-deficient
aromatic ring is necessary at R
1
; (ii) a five- or six-membered alicyclic ring is
optimal at R
2
; (iii) an H-bond donor-acceptor pair, either as part of an N-
acylurea or an amide of a 2-amino heterocycle with H-bond acceptor cap-
ability, is required at R
3
; and (iv) the (R) stereochemistry is preferred at the
chiral center.
Search WWH ::
Custom Search