Biomedical Engineering Reference
In-Depth Information
R
10
R
2
R
1
R
9
NH
2
O
R
12
R
6
R
3
N
N
N
R
7
N
R
4
R
5
O
R
8
R
11
9.16
Cl
Cl
NH
2
H
N
NH
2
N
HN
N
N
O
O
HN
O
O
HN
9.18
O
9.17
NH
2
Figure 9.3
KLK1 inhibitors. R
1
and R
2
¼
H, OH, (C
1-10
)alkyl, (C
1-6
)alkoxy, (C
2-6
)
alkenyl, (C
3-10
)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C
1-4
)alkyl
and heteroaryl(C
1-4
)alkyl. R
3
¼
H, (C
1-10
)alkyl, (C
2-6
)alkenyl. R
4
,R
5
¼
H,
(C
1-10
)alkyl, (C
2-6
)alkenyl, (C
3-10
)cycloalkyl, heterocycloalkyl, aryl, hetero-
aryl, aryl(C
1-4
)alkyl and heteroaryl(C
1-4
)alkyl. R
6
,R
7
¼
H, (C
1-10
)alkyl,
(C
2-6
)alkenyl, (C
3-10
)cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aryl(C
1-4
)
alkyl, aryl(C
2-4
)alkenyl, heteroaryl(C
1-4
)alkyl, -SO
2
(C
1-6
)alkyl, -SO
2
aryl,
and -SO
2
aryl(C
1-4
)alkyl. R
8
,R
9
,R
10
¼
H, (C
1-10
)alkyl, halogen, HO, (C
1-6
)
alkoxy, R
11
,R
12
¼
H, (C
1-6
)alkyl. In addition, R
6
and R
7
together with the
nitrogen atom to which they are attached, could form a four- to seven-
membered nitrogen-containing ring that may also contain N, O, and S, and
may carry a substitutionwith one or two substituents that could be (C
1-6
)alkyl,
(C
1-6
)alkoxy, halogen, CN, or HO, or the N-containing ring may be fused to
an aryl group. R
4
and R
6
together with the atoms to which they are attached
may form a saturated or unsaturated four- to seven-membered N-containing
ring which may also contain N, O, and S, and may carry a substitution
with one or two substituents that could be (C
1-6
)alkyl, (C
1-6
)alkoxy, halogen,
CN,andHO.R
5
may be absent, and R
4
and R
6
together with the atoms
to which they are attached may form a five-, six-, nine-, or 10-membered
mono- or bi-cyclic N-containing aromatic ring that may also contain N, O,
and S, and may carry a substitution with one, two, or three substituents
that could be (C
1-6
)alkyl, (C
1-6
)alkoxy, halogen, CN, HO, aryl, and COOR.
compounds inhibit KLK3/PSA in an irreversible manner through the generation
of a covalent acyl-enzyme complex with the active-site Ser.
110
Methodologies based on high-throughput screening (HTS) are currently
available and can be applied to screen for inhibitors against multiple enzymes or
the opposite. Recently, such methods were employed for screening libraries con-
taining approximately 50 000 different molecules for KLK3/PSA inhibition.
111
During this HTS, a high-a
nity inhibitor 9.22 with IC
50
300 nMwas identified.
111
