Potent inhibitors of farnesyltransferase and geranylgeranyltransferase-I

Article abstract of DOI:10.1016/S0960-894X(02)00154-3

Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC₅₀=2 nM) and GGPTase-I (IC₅₀=95 nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual FPTase/GGPTase-I inhibitors. 4-Trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano replacements.

Full text of DOI:10.1016/S0960-894X(02)00154-3

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1269–1273
Potent Inhibitors of Farnesyltransferase and
Geranylgeranyltransferase-I
Diem N. Nguyen,a,* Craig A. Stump,a Eileen S. Walsh,b Christine Fernandes,b
Joseph P. Davide,b Michelle Ellis-Hutchings,b Ronald G. Robinson,b
Theresa M. Williams,a Robert B. Lobell,b Hans E. Huberb and Carolyn A. Buserb
aDepartment of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
bDepartment of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA
Received 28 November 2001; accepted 22 February 2002
Abstract—Compound 1 has been shown to be a dual prenylation inhibitor with FPTase (IC50=2 nM) and GGPTase-I (IC50=95
nM). Analogues of 1, which replaced the cyanophenyl group with various biaryls, led to the discovery of highly potent dual
FPTase/GGPTase-I inhibitors. 4-Trifluoromethylphenyl, trifluoropentynyl, and trifluoropentyl were identified as good p-cyano
replacements. # 2002 Published by Elsevier Science Ltd.
Oncogenically mutated forms of Ras are found in
approximately 30% of all human cancers, including
30–50% of colon cancers and 90% of pancreatic can-
cers.1 Ras must associate with the cellular membrane in
order to have biological activity.2 While several post-
translational modifications to Ras help promote mem-
brane association, only prenylation is absolutely obli-
gatory. Because constitutively activated mutant Ras
protein is found in a variety of tumors, it has been
hypothesized that preventing Ras prenylation would
lead to inhibition of tumor growth.3 Of the three Ras
genes transcribed in human cells (H-, N-, and K-Ras),
K-Ras is the most commonly mutated gene.4 Since
K-Ras can be prenylated by either farnesyl protein
transferase (FPTase) or geranylgeranyl protein trans-
ferase type I (GGPTase-I), inhibition of both enzymes is
required to inhibit membrane association.5 Because
FPTase and GGPTase-I differ somewhat in their affi-
nities for protein substrates, finding potent inhibitors of
both enzymes represents a significant challenge.
that dramatic increases in FPTase potency could be
achieved with specifically substituted imidazoles relative
to the unsubstituted imidazole.8,9 A highly potent
FPTase inhibitor 1 was found to have inhibitory activity
50-fold more selective for FPTase (IC50=2 nM) than
GGPTase-I (IC50=95 nM) and was selected for human
clinical trials. Significant effort was put into optimizing
1 to find potent dual FTI/ GGTIs. Earlier studies have
shown that the p-cyanobenzylimidazole group is
uniquely active in conferring FPTase inhibitory activity
to compounds like 1.10 In an earlier study, replacing the
p-cyano with a hydrogen resulted in a loss of 5- to 10-
fold in FPTase potency.9 Herein, we describe the
syntheses and inhibitory profiles of a series of com-
pounds evaluating substituent effects on the phenyl
group, which led to the discovery of highly potent dual
FPTase/GGPTase-I inhibitors.
Numerous FPTase inhibitors (FTIs) have been reported
that mimic the tetrapeptide C-terminus of Ras (the
Ca1a2X motif).6,7 It had been demonstrated in prior
work that imidazole is a good cysteine surrogate and
A preliminary study involved the synthesis of sub-
stituted 1-(biarylmethyl)imidazoles whose inhibitory
activities were compared to those of 1-(4-cyanobenzyl)-
imidazole (data not shown). The more potent biaryls
were then incorporated into analogues of 1. Com-
pounds 5a–i (Table 1) were synthesized as shown in
Scheme 1. 4-Bromobenzylamine 2 was converted to the
imidazole methyl alcohol 3 according to a previously
*Corresponding author. Fax: +1-215-652-7310; e-mail: diem_
nguyen@merck.com
0960-894X/02/$ - see front matter # 2002 Published by Elsevier Science Ltd.
PII: S0960-894X(02)00154-3

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D. N. Nguyen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1269–1273
described method.11 Bromide 3 then underwent Suzuki
Table 1.
coupling with various substituted arylboronic acids,
followed by oxidation, and reductive alkylation to pro-
vide substituted biphenyl inhibitors 5. Alternatively, 3
was converted to the methyl chloride and alkylated with
1-(3-chlorophenyl)-2-piperazinone.12 Subsequent Suzuki
coupling introduced the substituted aryl group. Halo-
genated biaryls 5b–e were synthesized and activities
compared to 1 and 5a. The compounds were evaluated
for inhibition of FPTase13 and GGPTase-I14 in vitro.
The more potent compounds were also tested in a cell-
based assay (CRAFTI).15 These compounds (5b–e) had
modest in vitro inhibitory activity with respect to
FPTase ( IC50=8.7–35 nM) and except for 5b, were not
particularly active versus GGPTase-I (Table 1). meta-
and para-Trifluoromethyl substituents were also syn-
thesized (5f–h). Compounds 5f and 5g were less potent
than 1 and 5a against either FPTase or GGPTase-I.
However, the p-trifluoromethyl 5h was active with
respect to FPTase in vitro (IC50=5.7 nM) and had good
activity in cell culture (CRAFTI IC50=29 nM), and was
our first cyano group replacement that had good
potency in vitro and in vivo. In addition, its activity
versus GGPTase-I was similar to 1 (IC50=140 nM).
Compd
R
m
IC50 (nM)
FPTasea CRAFTIb GGPTase-lc
5a
5b
5c
1
1
1
12
1600
193d
576
1390
210e
8.7
17
8450e
5d
5e
5f
1
1
1
35
15
437
600
662d
3030
1340
2680
To enhance polarity and hopefully improve cell activity,
substituted heterobiaryls containing pyridine were
410
5g
1
3500
ND
1870
5h
1
1
1
1
1
1
2
5.7
29
ND
250
ND
159
12
140
1860
2300
560
5i
392
19
9a
Scheme 1. Reagents and conditions: (a) 1,3-dihydroxyacetone dimer,
KSCN, HOAc, n-BuOH, 50 ꢀC, 100%; (b) H2O2, TFA, MsOH, 0–
75 ꢀC, 40%; (c) SO3 pyr, Et3N, DMSO, 98%; (d) 1-(3-chlorophenyl)-
2-piperazinone, Na(OAc)3BH, ClCH2CH2Cl, rt, 26–28%; (e) SOCl2,
DMF, 0 ꢀC–rt, 86%; (f) 1-(3-chlorophenyl)-2-piperazinone, DIEA,
CH3CN, 0 ꢀC, 61%; (g) ArB(OH)2,Pd(PPh3)4, K2CO3, DME/H2O,
0.05 M, 80 ꢀC, 16–22%.
9b
52
9c
14
509
13a
13b
1.6
70e
0.17
1.2
151
aConcentration of compound required to inhibit FPTase-catalyzed
incorporation of [3H]FPP into recombinant Ras-CVIMby 50%. The
enzyme concentration was 1 nM. For IC50 <2 nM, enzyme con-
centration was 10 pM, n=2 otherwise noted.
bCell-based Radiotracer Assay for FarnesylTransferase Inhibition, in
which the concentration of compound required to displace 50% of
radiolabeled FTIs from FPTase in v-Ha-ras-transformed Rat1 cells,
n=1 otherwise noted.
cConcentration of compound required to inhibit 50% of the human
GGPTase-I catalyzed incorporation of [3H]GGPP into a biotinylated
peptide corresponding to the C-terminus of human K-Ras, n=2
otherwise noted.
Scheme 2. Reagents and conditions: (a) 1-(3-chlorophenyl)-2-piper-
azinone, Na(OAc)3BH, ClCH2CH2Cl, 44%; (b) 2-bromo-5-bromo-
methylpyridine, CHCl3, 40 ꢀC; (c) MeOH, reflux, 20%, two steps;
(d) ArB(OH)2, Pd(PPh3)4, K2CO3, DME/H2O, 80 ꢀC, 10–41%;
(e) CH3CN, 2-(4-chlorophenyl)-5-bromomethylpyridine, rt, 14%.
dn=2.
en=3.

D. N. Nguyen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1269–1273
1271
synthesized (9a–c, Scheme 2). 1-Trityl-4-imidazole-
carboxaldehyde 616 was reductively aminated with 1-(3-
chlorophenyl)-2-piperazinone to provide 7. Subsequent
alkylation with 2-(4-chlorophenyl)-5-(bromomethyl)-
pyridine17 gave 9a. Another way to make 9 was to
alkylate 7 with 2-bromo-5-(bromomethyl)pyridine to
form 8, followed by Suzuki coupling with aryl boronic
acids (9b–c). Compared to 1 and biphenyl 5h, 9a–c
showed decreased potency against both FPTase and
GGPTase-I (Table 1).
Additionally, 13a was a good inhibitor of GGPTase-I
with an IC50=70 nM. The activity of 13a indicates that
a methoxy group is tolerated at this position, either
helping to orient the two phenyl rings towards an
orthogonal conformation compared to 5h, or engaging
a favorable interaction with the receptor (no further
study was done). To further improve the potency of 13a,
the synthesis of 13b, which incorporated an ethyl link-
age between the imidazole and the piperazinone, was
undertaken. Compound 13b was prepared using chem-
istry strictly analogous to that described for the synthesis
of 19 in Scheme 4 (vide infra). Although 13b was 2-fold
less active versus GGPTase-I compared to 13a, it had
excellent activity (10-fold increase) against FPTase both
in vitro (IC50=0.17 nM) and in vivo (IC50=1.2 nM)
(Table 1). Compound 13b was also tested in PSN-1 cells
for its ability to inhibit farnesylation of the FPTase
substrate HDJ2 protein and geranylgeranylation of the
GGPTase-I substrate Rap1a protein.18 Processing of
HDJ2 was inhibited with EC50=28 nMand Rap1a
processing was inhibited with EC50=3400 nM.
Another strategy to improve inhibitory activity was to
influence the conformation of the aromatic rings by
introducing an ortho-methoxy group (5i, Table 1).
However, isomer 5i was at least 10-fold less active than
5h with respect to both FPTase and GGPTase-I. The
methoxy group was relocated to the other phenyl ring
producing 13a. The synthetic approach to 13a began by
converting 3-hydroxy-4-aminobenzoic acid 10 to its
methyl ester, followed by iodination and methylation to
afford 11 (Scheme 3). Iodide 11 was coupled with 4-tri-
fluoromethylphenyl boronic acid and reduced to alcohol
12 with LAH. Compound 12 was converted to the tri-
flate in situ and alkylated with 7 to provide 13a. The
activity of 13a was excellent with a 3-fold increase in
potency in FPTase (IC50=1.6 nM) and CRAFTI
(IC50=12 nM) compared to 5h.
Constrained macrocyclic analogues of 1 are highly
potent FTIs.19 In particular, imidazolylethylpiper-
azinone 20a was shown to be a very active FPTase inhi-
bitor in vitro (IC50=0.25 nM ) as well as in vivo (CRAFTI
IC50=0.19 nM). Interestingly, the 17-membered ring
macrocycle 20a had surprisingly good inhibitory activity
Scheme 3. Reagents and condtions: (a) HCl, CH3OH, reflux, 82%;
(b) NaNO2, KI, HCl, 0 ꢀC, 86%; (c) NaH, CH3I, rt, 100%; (d) 4-CF3-
PhB(OH)2, Pd(PPh3)4, Cs2CO3, DMF, 100 ꢀC, 92%; (e) LAH, THF,
rt, 49%; (f) Tf2O, DIEA, CH2Cl2, then 7, À78 ꢀC, 72%.
Table 2.
Compd
R
IC50 (nM)
FPTasea CRAFTIb GGPTase-lc
20a
20b
21a
21b
21c
21d
21e
CN
Br
4-CF3C6H4
H
0.25
1.2
2.1
8.0
10.3
6.1
3.1
0.19
2.0
16f
161
15.6
509
2480
Scheme 4. Reagents and conditions: (a) TFAA, Et3N, CH2Cl2, 0 ꢀC–
rt; (b) TrCl, Et3N, DMF, 0 ꢀC–rt; (c) NaOH, CH3OH, H2O, rt, 100%
for three steps; (d) DIEA, CH3CN, rt, 75–95%; (e) glycol aldehyde,
NaBH3CN, CH3OH, rt, 100%; (f) DTAD, n-Bu3P, THF, 0 ꢀC–rt, 40–
46%; (g) 4-bromo-3-fluorobenzyl alcohol, Tf2O, iPr2NEt, À78 ꢀC–rt;
(h) CH3OH, reflux; (i) Cs2CO3, DMSO, 0.05 M, 140 ꢀC, 18–22%,
three steps; (j) ArB(OH)2, Pd(PPh3)4, K2CO3, DME/H2O, 0.05 M,
80 ꢀC, 37%; (k) Bu3Sn-alkyne, Pd(PPh3)4, DMF, 120 ꢀC, 58%;
(l) n-Bu4Sn, PdClBn(PPh3)2, HMPA, 120 ꢀC, 5%.
1.1d
ND
ND
0.81d
0.48
CH3CH2CH2CH2
F3CCH2CH2CC
F3CCH2CH2CH2CH2
4.8
60
a,b,c,dSee corresponding footnotes in Table 1.
fn=5.

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D. N. Nguyen et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1269–1273
versus GGPTase-I (IC50=16 nM) compared to analo-
gous 16-membered ring-contracted macrocycles.19 To
further increase GGPTase-I activity, modifications to
20a were investigated. As in the linear series, various
groups were introduced to replace the p-cyano group.
The synthetic route to obtain 20a–b and 21a–e is
described in Scheme 4. The trityl histamine 15 was
available from histamine by a protection–alkylation–
deprotection sequence. 15 was alkylated with 1619 to
provide 17. Reductive alkylation with glycol aldehyde
dimer, followed by Mitsunobu-type ring closure of
the piperazinone12 yielded 18. Alkylation of 18 with
4-bromo-3-fluorobenzyl alcohol followed by deprotec-
tion of the imidazole gave 19. SNAr macrocyclization of
19 proceeded to provide 20, even with the marginally
activated 3-fluoro-4-bromobenzyl group.20 The 4-bro-
mophenyl macrocycle 20b underwent either Suzuki
coupling with p-trifluoromethylphenyl boronic acid
(21a) or Stille coupling with tetra-n-butyl tin (21c) or
tributylalkynyl tin (21d). During purification of 21c, a
small amount of reduced by-product 21b was isolated.
Alkyl-substituted 21e was obtained from palladium
catalyzed hydrogenation of 21d.
identified 4-trifluoromethylphenyl (5h, 13a, and 13b) as
a good p-cyano replacement. In the constrained macro-
cylic analogues of 20a, excellent inhibitory activities
against both FPTase and GGPTase-I were obtained
with 4-trifluoromethylphenyl, trifluoropentynyl and tri-
fluoropentyl substituents. Both series showed effective
functional inhibition of FPTase and GGPTase-I activity
in cell culture.
Acknowledgements
The authors wish to thank K. D. Anderson, A. B.
Coddington, G. M. Smith, H. G. Ramjit, C. W. Ross
III, B.-L. Wan, and M. M. Zrada for analytical support,
and C. J. Dinsmore and S. L. Graham for critical reading
of the manuscript.
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