1136
H. Y. Zhu et al. / Bioorg. Med. Chem. Lett. 20 (2010) 1134–1136
nitrogen. The binding of the tricyclic core is similar to previous
compounds lacking the zinc binding motif.12 Carbonyl of the Boc
group also contributes to the binding with interaction with surface
H2O molecule.
Further modifications on the piperazine moiety of 10a were car-
ried out with representative analogs shown in the Table 3. Urea
and carbamate are suitable substitutions at piperazine 1-N as indi-
cated in the X-ray structure with the carbonyl group contributing
to binding. Various sized alkyl and aromatic groups were generally
tolerated. Most compounds are sub nanomolar FPT inhibitors with
low single digit nM inhibitors in soft agar assays.
The hERG activity of compound 12 was assessed and found to
be 37% inhibition at 1
considering its sub nM FPT cellular potency. This compound had
low rat PK (10 mpk, 0–6 h, AUC = 0.1 M). However rat PK on car-
bamate analogs were generally good with AUC = 2.57 M h
lM. It provided a large therapeutic window
l
l
(10 mpk, 0–6 h) for compound 10a (17% hERG inhibition at
300 nM).
In conclusion, we discovered a novel series of potent FPT inhib-
itors featuring C-linked imidazole as the active site Zn binder. We
also demonstrated that the methylene linker carbon was amend-
able to substitutions. DMPK properties could be modulated with
these groups with notable reduction in hERG inhibition. Optimiza-
tion efforts on this series will be reported in future papers.
Figure 2. Structure of 10a (yellow sticks) bound to FPT. The zinc (Orange sphere),
FPP (blue surface) and several specific interactions (white lines) are illustrated.
References and notes
1. (a) Taveras, A. G.; Kirschmeier, P.; Baum, C. M. Curr. Top. Med. Chem. 2003, 3,
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2004, 7, 478; (c) Bell, I. M. J. Med. Chem. 2004, 47, 1869.
Table 3
FPT, soft agar activities of C-imidazole benzocycloheptapyridine derivatives
2. (a) Adjei, A. A.; Erlichman, C.; Davis, J. N.; Cutler, D. L.; Sloan, J. A.; Marks, R. S.;
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J. Biol. Chem. 1995, 270, 30611.
N
N
OH
Cl
N
N
N
O
R
Compd
R
FTase IC50 (nM)
0.38
Soft agar IC50 (nM)
0.5
O
10a
4. Njoroge, G. Manuscript in progress. Examples of bridgehead piperazine
compounds with enhanced FPT activities, see: Njoroge, F. G.; Vibulbhan, B.;
Pinto, P.; Strickland, C.; Bishop, W. R.; Nomeir, A.; Girijavallabhan, V. Bioorg.
Med. Chem. Lett. 2006, 16, 984.
5. (a) Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.; Cho, Y.; Chong, S.;
Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S. H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.;
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CN
12
13
N
H
0.5
0.5
2.7
N
H
0.13
N
H
14
15
0.47
0.4
18
6. Reid, T. S.; Beese, L. S. Biochemistry 2004, 43, 6877.
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N
H
0.5
8. Zhu, Hugh Y.; Njoroge, F. George; Cooper, Alan B.; Guzi, Timothy; Rane,
Dinanath F.; Minor, Keith P.; Doll, Ronald J.; Girijavallabhan, Viyyoor M.;
Santhanam, Bama; Pinto, Patrick A.; Vibulbhan, Bancha; Keertikar, Kartik M.;
Alvarez, Carmen S.; Baldwin, John J.; Li, Ge; Huang, Chia-yu; James, Ray A.;
Bishop, W. Robert; Wang, James J.-S.; Desai, Jagdish A. U.S. Pat. Appl. Publ.
2004, US 2004122018.
16
17
18
19
0.75
1.0
0.5
1.0
1.0
0.5
O
O
0.3
9. Zhu, H.Y. et al. unpublished results.
O
O
10. Siu, T.; Li, Y.; Nagasawa, J.; Liang, J.; Tehrani, L.; Chua, P.; Jones, R. E.; Defeo-
Jones, D.; Barnett, S. F.; Robinson, R. G. Bioorg. Med. Chem. Lett. 2008, 18, 4191.
11. Crystallographic data for the inhibitor 10a-FTase complex shown in Figure 2
have been deposited with the RCSB (code RCSB056400) Protein Data Bank as
PDB ID 3KSQ.
0.76
12. Strickland, C. L.; Weber, P. C.; Windsor, W. T.; Wu, Z.; Le, H. V.; Albanese, M. M.;
Alvarez, C. S.; Cesarz, D.; del Rosario, J.; Deskus, J.; Mallams, A. K.; Njoroge, F.
G.; Piwinski, J. J.; Remiszewski, S.; Rossman, R. R.; Taveras, A. G.; Vibulbhan, B.;
Doll, R. J.; Girijavallabhan, V. M.; Ganguly, A. K. J. Med. Chem. 1999, 42, 2125.
N3 nitrogen. The imidazole 1N-methyl is packed against FPP. The R
configuration places the hydroxyl group towards solvent in a posi-
tion to make an intra-molecular hydrogen bond to the piperazine