S. D. P. Baugh et al. / Bioorg. Med. Chem. Lett. 25 (2015) 3836–3839
3837
Table 1
O
F
SAR of amide analogs as inhibitors of delta-5 desaturase
F
F
O
O
F
O
N
F
O
X
O
H
H
N
O
N
H
Z
O
O
N
H
O
F
F
F
NH2
Y
3
2
O
Compound
X
Y
Z
IC50 (nM)
O
1
5
6
7
8
9
10
11
12
NH2
NH2
NH2
OH
NH2
NH2
OH
H
H
H
H
F
Cl
F
58
516
843
174
67
34
15
925
H
N
NH2
O
i-Pr
Cl
Cl
Cl
Cl
Cl
Cl
N
H
Cl
OCH3
OCH2CH3
5
4
OH
Figure 1. Representative literature described delta-five desaturase inhibitors.
IC50 of 58 nM (see Table 1). Moving the chlorine atom of compound
5 from the meta position to either the ortho- or para-position gave
compounds with markedly lower potency (39% and 36% enzyme
quinazoline, and naphthalene derivatives 12–14, all showed good
potency, whereas the furo[3,2-c]pyridyl derivative 15 was much
less active. Thieno[3,2-d]pyrimidine 16 showed good activity,
whereas the regioisomeric thieno[2,3-d]pyrimidine 17 was sub-
stantially less potent. The indane, compound 18, was reasonably
potent as the racemate, and the indazole, compound 19, also
showed good potency. From these, as well as other ring-con-
strained analogs not shown, the indazole derivative 19 was
selected for further investigation. With the previous amide and
phenol series’ showing improved activity upon substitution upon
the left-hand aromatic ring, we next set about producing substi-
tuted analogs of 19.
inhibition, respectively, at 1 lM compound concentration), thus
our work focused primarily on changes at the meta position.
Examples of the functional group variations that we employed
included changing the chlorine atom to a fluorine or isopropyl
group, Table 1, compounds 6 and 7, both of which resulted in sig-
nificantly reduced activity. Di-substituted right-hand side deriva-
tives of compound 5 were also pursued, however they too
resulted in reduced activity—for example, 3,5-dichloro (245 nM),
and 3-chloro-4-fluoro (155 nM).
Maintaining the preferred amide linker and right-hand side aro-
matic ring, we next made changes to the left-hand ring. Moving
from X = amino to X = hydroxyl (5 vs 8) showed a slight drop in
activity. Attempts to replace the amino or hydroxyl with other
functionalities such as methyl, cyano, and chloro all provided
derivatives with significantly lower activity, and moving the amino
group around the left-hand ring demonstrated that the optimal
position for the amino group was at the 2-position (for instance,
the 3-amino derivative showed only 54% enzyme inhibition at
The substituted indazole derivatives were synthesized either
via displacement of the 3-halo indazole with the appropriate ani-
line, coupling of the requisite 3-amino indazole with the appropri-
ate aryl boronic acid in the presence of copper(II) acetate, or by
palladium catalyzed aryl amination, Scheme 3.8
In some cases, replacement of the Z chloro substituent with flu-
orine did still produce active molecules, such as 20, but this was
not general, and thus chloro was the Z group of choice, Table 3.
As expected from our previous work, substitutions at the 4-, 6-,
and 7-position of the indazole ring with groups larger than fluorine
were almost exclusively detrimental to the activity against the tar-
get, with a notable exception being the 7-chloro derivative of com-
pound 19 which showed an IC50 of 33 nM. Hence, we focused on
variations at the 5-position. Introduction of fluorine at the 5-posi-
tion, compound 21, maintained potency, whereas dichloro deriva-
1 lM compound concentration). Addition of the Y-substituent at
the 5-position resulted in increased potency (10 and 11). Steric
effects were also found, with a drastic loss in potency seen when
changing from 5-methoxy to 5-ethoxy (11 vs 12).
After exploring the SAR with amide based derivatives, we found
that they possessed poor metabolic stability and pharmacokinetics.
Since we believed that the activity of the compounds was related
to a six-membered hydrogen bond between the amide carbonyl
and the anilinic/phenolic functionality.13,14 we next focused on
making cyclized versions of these derivatives.
The syntheses of the initial ring-constrained analogs were car-
ried out by following one of the four methods shown in
Scheme 2. The compounds were either synthesized by SNAr dis-
placement of an aryl halide, Buchwald–Hartwig aryl amination,
copper(II) acetate mediated coupling of an aryl amine (Chan–Lam
coupling), or by reaction neat of the chloro-indazole with the ani-
line hydrochloride.8
tive 22 showed
a substantial improvement in activity, and
brominated compound 23 resulted in an appreciable increase in
activity compared to compound 19. Methyl derivative 24 was
highly potent, whilst the trifluoromethyl variation 25 resulted in
diminished activity. Methoxy substituted 26 was also very active,
whilst trifluoromethoxy-containing 27 was not.
From these indazole derivatives, four compounds, 19, 20, 21
and 26 were selected to be tested in an in vivo liver enzyme inhi-
bition experiment—delta-5 desaturase is highly expressed in the
mammalian liver.6 Each compound was given orally along with
vehicle control, using a PEG/Solutol (20:80) dosing vehicle, to mice
(n = 4) at a dose of 30 or 60 mg/kg, then 30 min later 14C-di-homo-
gamma-linolenic acid (DGLA) was given using an intraperitoneal
As can be seen from Table 2, a variety of different bicyclic sys-
tems as ring-constraints were well tolerated. Quinoline,
Scheme 1. Reagents and conditions: (a) aniline, EtOH, 100 °C; (b) aniline, PCI3, PhMe, 120 °C. For lists of Y and Z see Table 1.
Baugh, Simon D.P.
