The optimized compound 20 which is one log unit more potent
on target than compound 17 shows relatively greater reduction of
the activity on the other kinases and therefore can be considered
to be more selective than compound 17. The (S)-5,5-
dimethyltetrahydro-furan-3-ylmethyl group showed the same
potential as the benzyl starting point to confer general kinase
selectivity to compound 2. However, this group did not
substantially improve the hERG inhibition liability of the parent
compound 1 (IC50 = 0.42 vs 0.13 μM in a hERG dofetilide
competition binding assay) while compound 17 showed a
reduced inhibition (IC50 = 3.6 μM) possibly linked to a decreased
lipophilicity as compared to compound 1 (cLogP: 3.0 vs 4.4,
respectively). Compound 20, in addition to have a good water
solubility, displayed a high permeability at neutral pH, and
above, in a parallel artificial membrane permeability assay and
showed no interference at 10 μM with 3 major human
cytochrome P450 drug metabolizing isoforms (2D6, 2C9, 3A4).
Synthesis of compounds 3-4, 6-7 and 10-20 was achieved by
standard Mitsunobu reaction of compound 2 with the suitable
commercially
available
alcohol
or
(S&R)-(5,5-
dimethyltetrahydrofuran-2-yl)methanol
described
in the
literature.8 Palladium on charcoal catalyzed hydrogenolysis of
compound 19 yielded compound 2. Compound 8 was obtained
subsequently by tert-butyl deprotection of compound 12 in
aqueous TFA. Compounds 5 and 9 were obtained by alkylation
of compound 2, after deprotonation with NaH, with the
corresponding commercial bromo reagent (Scheme 1).
NH2
NH2
NH2
N
N
N
OBn
OH
OR
N
N
N
a
b , c or d
N
N
N
1
2
3 20
-
N
N
N
NVP-AEW541
Scheme 1. Reagents and conditions: (a) Pd-C 10%, H2, 0.15 M in THF-
MeOH 1:1, rt, 24 h, 96%; (b) ROH (1.1-1.3 eq.), DIAD (1.45-1.6 eq.), PPh3
(1.45-1.6 eq.), 0.2 M in THF, 15-23 h, rt, 17-63%; (c) Only for compound 12
to obtain compound 8: 0.9 M 49% aqueous TFA, rt, 18.5 h, 61%; (d)
Compound 5 and 9: 60% NaH in oil (1 eq.), 0.2 M in DMF, rt, 10 min then
RBr (1 eq.), rt, 60-80 min, 27-42%.
In conclusion, we have shown that the benzyloxy group of
NVP-AEW541 can be advantageously replaced by a 2-(cyclic-
ether)-methylether moiety allowing redirection of the metabolism
to avoid formation of the unwanted pankinase inhibitor
compound 2, while maintaining an adequate kinase selectivity
and on target potency. The further optimization of the series as
IGF-1R inhibitors is discussed in the following letter.10
Acknowledgments
The authors would like to thank Reiner Aichholz, Werner
Gertsch, Jérome Dayer for human liver microsome metabolic
investigations and Christoph Mura and Christian Ragot for their
excellent technical assistance.
Figure 3. X-ray co-crystal structure of Ins-R in complex with compound 6
(ATP site). The two hydrogen bonds with K1057 formed by the 1,4-diether
group are indicated by magenta lines (PDB code: 5HHW).
Table 2. Biochemical inhibition of IGF-1R for compounds 1–
20.
References and Notes
Compounds
R substituents
IGF-1R
Inhibition
IC50, mMa
0.061
0.42
1. Pollak, M. N.; Perdue, J. F.; Margolese, R. G.; Baer, K.;
Richard, M. Cancer Lett. 1987, 38, 223.
2. Tognon, C. E.; Sorensen P. H. B. Expert Opin. Ther.
Targets 2012, 16, 33.
1
2
Benzyl
H
3. Yee, D. Clin. Cancer Res. 2015, 21, 667.
3
4
5
6b
7b
8
(rac)-1-phenylethyl
cyclohexylmethyl
methoxyethyl
3.7
0.55
2.0
0.080
0.13
7.9
0.63
0.31
0.26
0.16
0.49
0.37
1.9
4. García-Echeverría, C.; Pearson, M. A.; Marti, A.; Meyer,
T. ; Mestan, J.; Zimmermann, J.; Gao, J.; Brueggen, J.;
Capraro, H.-G.; Cozens, R.; Evans, D.B.; Fabbro, D.; Furet.
P.; Graus Porta D.; Liebetanz, J.; Martiny-Baron, G.; Ruetz,
S.; Hofmann, F. Cancer Cell 2004, 5, 231.
(R)-tetrahydropyran-2-ylmethyl
(S)- tetrahydropyran-2-ylmethyl
hydroxyethyl
9
ethoxyethyl
propyloxyethyl
isopropyloxyethyl
tert-butyloxyethyl
cyclopentyloxyethyl
isopentyloxyethyl
cyclobutylmethyl
5. Favelyukis, S.; Till, J. H.; Hubbard, S.R.; W. Todd
Miller, W.T. Nat. Struct. Biol. 2001, 8, 1058.
10
11
12
13
14
15
16
17
18
19
20
6. Katsuhiro, I.; Akihiro; A. J. Phys. Chem. 1992 96, 7934.
7. Our attempts at co-crystallizing the IGF-1R kinase with
one of the 1,4 diether derivatives failed. The residues of the
ATP site in contact with inhibitors are absolutely conserved in
the IGF1R and InsR kinases.
8. Harrowven, D. C.; Dennison, S. T.; Haymard, J. S.
Tetrahedron Lett. 1994, 35, 7467.
9. Slade, J.; Bajwa, J.; Liu, H; Parker, D.; Vivelo, J.; Chen,
G.-P.; Calienni, J.; Villhauer, E.; Prasad, K.; Repic, O.;
Blacklock, T.J. Org. Process Res. Dev., 2007, 11, 825.
10. Fairhurst, R. A.; Marsilje, T. H.; Stutz, S.; Boos, A.;
cyclopentylmethy
0.84
(S)-tetrahydrofuran-2-ylmethyl
(R)-tetrahydrofuran-2-ylmethyl
(R)-5,5-dimethyltetrahydro-furan-2-ylmethyl
(S)-5,5-dimethyltetrahydro-furan-2-ylmethyl
0.080
0.110
0.060
0.0089
aGeometric mean of duplicates.
bSeparated from the racemic mixture by chiral preparative HPLC (>99.9%ee)