Chemistry Reference
In-Depth Information
0.35
0.30
0.25
9
Desired drug
properties
6
8
A
7
21
7
6
19
5
11
17
4
8
5
3
1
1
Heavy atom count
Approximate mw
10
20
30
40
50
60
150
300
450
600
750
Figure 11.7
Affinity versus heavy atom count for selected compounds. Lines illustrate profiles
at fixed ligand efficiency (0.35, 0.30, 0.25) over the range of affinity and heavy atom count.
Point
A
designates an idealized compound with 36 heavy atoms (approximate MW 500Da )
and affinity 10 nM). Numbers correspond to compounds described in the text.
properties, DMPK properties, selectivity, etc. All these features together contribute to the
final assessment of drug-likeness.
These considerations are further illustrated as follows. The peptidic inhibitor OM99-2
(
6
, Figure 11.8) binds with very high affinity (1.6 nM) to BACE,
[
17
]
but because of its high
molecular weight each atom appears to make only a relatively small contribution to the
overall binding. This compound has a ligand efficiency of only 0.19; this is indicated in
Figure 11.7. Compound
7
was discovered by the Elan group
[
39
]
and demonstrated by Astex
O
OH
H
N
O
O
NH
OH
OH
H
H
Ala-Glu-Phe
Glu-Val-Asn
N
O
O
NH
O
6
7
8
OM99-2
K
i
=
1.6 nM
a
MW
=
893, HAC
=
63
LE 0.19
IC
50
= 138
m
M
b
MW 342; HAC 25
LE
=
0.21
IC
50
= 230 nM
b
MW 531, HAC 39
LE
=
0.23
Figure 11.8
Structure of OM99-2 and related peptidic inhibitors.
a
Reported by Hong
et al
.
17
b
Determined by SPR spectroscopy.
