1574
Y. Tong et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1571–1574
Table 5. SAR of pyridyl compounds 26
Acknowledgements
X-ray crystallographic data were collected at beamline
17-ID in the facilities of the Industrial Macromolecular
Crystallography Association Collaborative Access
Team (IMCA-CAT) at the Advanced Photon Source.
These facilities are supported by the compaines of the
Industrial Macromolecular Crystallography Association
through a contract with Illinois Institute of Technology
(IIT), executed through IIT’s Center for Synchrotron
Radiation Research and Instrumentation. Use of the
Advanced Photon Source was supported by the US
Department of Energy, Basic Energy Sciences, Office of
Science, under Contract No. W-31-109-Eng-38.
Compd
R
FTase
IC50
(nM)
GGTase-I
IC50
(nM)
RP
EC50
(nM)
PKa
F
(%)
26a
26b
26c
26d
26e
26f
3.9
>10,000
1700
510
19
—
—
0.82
0.18
0.18
0.51
0.71
1.8
2.0
1.2
4.0
2.2
References and Notes
1. (a) Hunter, T. Cell 1997, 88, 333. (b) McCormick, F. Nat-
ure 1993, 363, 15. (c) Barbacid, M. Annu. Rev. Biochem. 1987,
56, 779.
2. Reiss, Y.; Goldstein, J. L.; Seabra, M. C.; Casey, P. J.;
Brown, M. S. Cell 1990, 62, 81.
3. (a) End, D. W. Invest. New Drugs 1999, 17, 241. (b) Wil-
liams, T. M.; Dinsmore, C. J. Adv. Med. Chem. 1999, 4, 273.
(c) Rowinsky, E. K.; Windle, J. J.; Von Hoff, D. D. J. Clin.
Oncol. 1999, 17, 3631. (d) Qian, Y.; Sebti, S. M.; Hamilton,
A. D. Biopoly. 1997, 43, 25.
4. (a) Prendergast, G. C. Curr. Opin. Cell Biol. 2000, 12, 166.
(b) Lebowitz, P. F.; Casey, P. J.; Prendergast, G. C.; Thissen,
J. A. J. Biol. Chem. 1997, 272, 15591.
73b
1100
1200
4800
90b,d, 56c
—
93b, 19c
5. (a) Ayral-Kaloustian, S.; Salaski, E. Curr. Med. Chem.
2002, 9, 1003. (b) Gotlib, J.; Dugan, K.; Katamneni, U.; Srid-
har, K.; Wright, A. J.; Thibault, A.; Ryback, M. E.; Green-
berg, P. L. Program/Proceedings, 38th Am. Soc. Clin. Oncol.
Annual Meeting, Orlando, FL, 18–21 May 2002. Am. Soc.
Clin. Oncol.: Alexandria, VA, 2002 (Abstract #14, see pro-
gram document for more references).
26g
26h
0.45
44
1400
42
6.0
—
—
—
6. Lobell, R. B.; Omer, C. A.; Abrams, M. T.; Bhimnathwala,
H. G.; Brucker, M. J.; Buser, C. A.; Davide, J. P.; deSolms, S. J.;
Dinsmore, C. J.; Ellis-Huntchings, M. S.; Kral, A. M.; Liu, D.;
Lumma, W. C.; Machotka, S. V.; Rands, E.; Williams, T. M.;
Graham, S. L.; Hartman, G. D.; Oliff, A. I.; Heimbrook, D. C.;
Kohl, N. F. Cancer Research 2001, 61, 8758.
7. See 5(a) for structures of imidazole-containing FTIs devel-
oped by Bristol-Myers Squibb, Merck, and Janssen.
8. We will disclose detailed results in different accounts.
9. Molina, P.; Fresneda, P. M.; Garcia-Zafra, S. Tetrahedron
Lett. 1996, 37, 9353.
26i
26j
27e
1.9
>10,000
5500
88
7.4
17
—
—
—
0.16
1.8
>10,000
10. Rocca, P.; Cochennec, C.; Marsais, F.; Thomas-dit-
Dumont, L.; Mallet, M.; Godard, A.; Queguiner, G. J. Org.
Chem. 1993, 58, 7832.
11. Farnesyl diphosphate (FPP) was replaced by hydroxyl
farnesyl phosphate (HFP) in this study.
12. See PDB ID 1NT1 for coordinates.
a1 mg/kg single dose.
bDog PK.
cMonkey PK.
dOther oral PK data: t1/2=7.6 h; Cmax=0.26 mcg/mL; Tmax=1.0 h;
AUC=2.8 mcg.h/mL.
eSynthesized from the reaction of 6 and 15.