Aryl tetrahydropyridine inhibitors of farnesyltransferase: Bioavailable analogues with improved cellular potency

Article abstract of DOI:10.1016/S0960-894X(03)00094-5

Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavail

Full text of DOI:10.1016/S0960-894X(03)00094-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 1363–1366
Aryl Tetrahydropyridine Inhibitors of Farnesyltransferase:
Bioavailable Analogues with Improved Cellular Potency
Stephen L. Gwaltney, II,* Stephen J. O’Connor, Lissa T. J. Nelson, Gerard M. Sullivan,
Hovis Imade, Weibo Wang, Lisa Hasvold, Qun Li, Jerome Cohen, Wen-Zhen Gu,
Stephen K. Tahir, Joy Bauch, Kennan Marsh, Shi-Chung Ng, David J. Frost,
Haiying Zhang, Steve Muchmore, Clarissa G. Jakob, Vincent Stoll, Charles Hutchins,
Saul H. Rosenberg and Hing L. Sham
Pharmaceutical Discovery, R47B, Building AP-10, Abbott Laboratories, Abbott Park, IL 60064-6101, USA
Received 12 August 2002; accepted 2 January 2003
Abstract—Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to
evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bio-
available aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these
compounds will be discussed.
# 2003 Elsevier Science Ltd. All rights reserved.
In the preceding paper, we described the discovery of a
novel class of farnesyltransferase inhibitors (FTIs) that
contain a tetrahydropyridine (THP) core. In this letter,
we disclose further examples from this series, many of
which are potent in a cellular assay and several of which
are bioavailable. As explained before, we sought a
selective inhibitor of FT. Initially, all our compounds
were tested for their ability to inhibit FT and GGT-I in
vitro. Potent compounds were then tested in a cellular
assay that measured inhibition of the farnesylation of
Ras (Ras processing, RP).1 Selected compounds were
then tested for pharmacokinetics.2
In an effort to improve upon this compound, we exam-
ined several other series of tetrahydropyridine contain-
ing FTIs. One series related to the previously described
glycine derivatives is represented by the ureas in Scheme
1. The synthesis of these analogues begins with the
known compounds 2 and 3. Reductive amination pro-
vided secondary amine 4. In situ formation of the car-
bamoyl chloride followed by addition of the
tetrahydropyridine core gave the urea. These lower
homologues of the glycine derivatives show markedly
improved potency for FT inhibition. These compounds
are also selective for FT over the related enzyme ger-
anylgeranyltransferase-I (GGT-I). Unfortunately, none
of these compounds was sufficiently potent in the cel-
lular assay.
The best compound identified in the previous work is
the histidine derivative 1 (Fig. 1). This compound is
potent and selective for FT, but suffers loss of potency
in the cellular assay.
We next prepared an analogue with a one carbon linker
attaching the imidazole and cyanophenyl pharmaco-
phores to the tetrahydropyridine core. This compound
was prepared by alkylating the THP with the secondary
chloride derived from 11. 12 demonstrated excellent
potency for farnesyltransferase and was also potent in
the cellular assay, but was not as selective as previous
compounds (Scheme 2).
Figure 1. Compound 1.
To examine a homologue of compound 12, we found it
convenient to install a hydrazine unit in our inhibitor.
The synthesis of this compound is shown in Scheme
3 and makes use of the method developed for the
*Corresponding author. Tel.: +1-858-731-3562; fax: +1-858-550-
0526; e-mail: stephen.gwaltney@syrrx.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00094-5

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Scheme 1. Urea derivatives.
Scheme 4. Imidazoleacetic acid derivatives.
Compound 24 showed excellent potency both in enzy-
matic and in cellular assays and was selective for FT.
However, the compound has poor pharmacokinetics
with an oral bioavailablility of 10% and a half-life of
0.7 h in dogs.
A crystal structure of 24 bound to FT was obtained
(Fig. 2).4 Surprisingly, this compound binds in a mark-
edly different manner from ABT-839 and other THP
inhibitors examined. While the imidazole is still bound
to zinc, the tetrahydropyridine core and the cyano-
benzyl unit have switched places in the active site.
Scheme 2. Methine linked inhibitor 12.
tetrahydropyridine core described in the preceding article.
Compound 22 demonstrated excellent potency both in
enzymatic and in cellular assays and showed good
selectivity for FT. In addition, this compound is orally
bioavailable in dogs (F=27%) with a half-life of 1.2 h.
The crystallography and biological results for 24 led us
to prepare the homologue with another carbon in the
We also examined analogues based on imidazoleacetic
acid, as shown in Scheme 4. The known acid 233 was
coupled to the THP core using HATU to provide 24.
Figure 2. Superimposed X-ray crystal structures of ABT-839 and 24 in
the FT active site.
Scheme 3. Hydrazine containing FTI 22.

S. L. Gwaltney, II et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1363–1366
1365
linker and an analogue where the naphthyl unit was
moved to the cyanobenzyl group. The synthesis of these
compounds is shown in Scheme 5. The known acid 275
was coupled to the THP core using EDC. This amide
was then treated with 4-cyanobenzyl bromide to affect
quaternization of the imidazole nucleus. Methanolysis
of this salt led to 29. The preparation of 35 begins with
the enol intermediate from the THP core synthesis
described in the preceding paper. Treatment of 30 with
trimethylsilyldiazomethane gave the methyl ether, which
could be converted to the amine salt using ACE-Cl as
before. To prepare the coupling partner for this amine,
the known ester 32 was first alkylated with bromide 33.6
Methanolysis and saponification gave the imidazoleace-
tic acid which was then coupled to the THP using
HATU. Gratifyingly, both 29 and 35 were potent and
selective for FT; however, neither realized improvement
over 24 in cellular potency.
Scheme 6. Tertiary alcohol 39.
as shown in Scheme 6. Alkylation of the THP core with
the commercially available 36 gave ketone 37. Addition
of the ceriumreagent 38 led to production of the ter-
tiary alcohol 39. This compound showed impressive
potency in enzymatic and cellular assays and is
approximately 1000 fold selective for FT over GGT-I.
This compound also demonstrates reasonably good
pharmacokinetics with an oral bioavailability of 57%
and a half-life of 1.7 h in dogs.
Upon examination of the SAR for the compounds thus
far, one notes that compounds 12 and 22 are two of the
best. With this in mind, we sought to prepare a hybrid
of these compounds by using an ethylene linker. This
was accomplished by preparing the tertiary alcohol 39
In summary, the aryl tetrahydropyridine containing
farnesyltransferase inhibitors described here7 represent
a significant improvement over previous compounds.
Many are potent and selective inhibitors of FT. Several
also possess good cellular activity and oral bioavail-
ability. X-ray crystallography proved valuable for
understanding the interactions of these inhibitors with
FT and for the design of new analogues.
Acknowledgements
Crystallographic data were collected at beamline 17-ID
in the facilities of the Industrial Macromolecular Crys-
tallograpy Association Collaborative Access Team
(IMCA-CAT) at the Advanced Photon Source. These
facilities are supported by the companies of the Indus-
trial 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.
References and Notes
1. Assay methods described in: Vogt, A.; Qian, Y.; Blas-
kovich, M. A.; Fossum, R. D.; Hamilton, A. D.; Sebti, S. M.
J. Biol. Chem. 1995, 270, 660.
2. Pharmacokinetic properties were determined either by tradi-
tional methods or through combinatorial studies where three
compounds and a reference compound were administered at a
dose of 1 mg/kg in the appropriate species for a total dose of
4 mg/kg. Plasma concentrations were determined by HPLC-MS.
3. Anthony, N. J.; Gomez, R. P.; Schaber, M. D.; Mosser,
S. D.; Hamilton, K. A.; O’Neil, T. J.; Koblan, K. S.; Graham,
Scheme 5. Analogues of 24.

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S. L.; Hartman, G. D.; Shah, D.; Rands, E.; Kohl, N. E.;
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4. Coordinates deposited (PDB 1N9A).
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7. All compounds reported have physical data consistent with
the assigned structures.