Synthesis of 1H-pyridin-2-one derivatives as potent and selective farnesyltransferase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2004.07.004

The synthesis and biological evaluation of two novel series of potent and selective FTase inhibitors are described. Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2- carbonitrile was established. The structure of compound 5c was confirmed by X-ray crystallography.

Full text of DOI:10.1016/j.bmcl.2004.07.004

Bioorganic& Medicinal Chemistry Letters 14 (2004) 4603–4606
Synthesis of 1H-pyridin-2-one derivatives as potent and selective
farnesyltransferase inhibitors
Le Wang,* Nan-Horng Lin, Qun Li, Rodger F. Henry, Haiying Zhang, Jerome Cohen,
Wen-Zhen Gu, Kennan C. Marsh, Joy L. Bauch, Saul H. Rosenberg and Hing L. Sham
Cancer Research, R-47B, Global Pharmaceutical Research & Development, Abbott Laboratories, 100 Abbott ParkRoad,
Abbott Park, IL 60064-6101, USA
Received 13 May 2004; revised 1 July 2004; accepted 2 July 2004
Available online 27 July 2004
Abstract—Two novel series of potent and selective FTase inhibitors have been synthesized using structure-based design. Medicinal
chemistry efforts led to the discovery of compound 4e with potent cellular activity and good oral bioavailability in dog. A synthetic
route toward novel heterocycles 1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbonitrile was established. The structure of
compound 5c was confirmed by X-ray crystallography.
Ó 2004 Elsevier Ltd. All rights reserved.
Mutated Ras proteins are found in over 30% of human
cancers. To participate in the transduction of extracell-
uar mitogenicsignals to the nucleus, Ras proteins need
to be S-farnesylated by farnesyltransferase (FTase). It
has been shown that inhibitors of FTase can stop pro-
tein farnesylation and suppress the growth of Ras-
dependent tumor cells both in cell culture and in
rodents. Emerging evidence suggests that Ras may not
be the only substrate of FTase associated with oncogen-
esis. While the exact mechanism of FTase inhibitors
remains elusive, FTase inhibitors are promising agents
in cancer therapy due to their excellent efficacy and
low systemic toxicity in pre-clinical animal models.
Extensive drug discovery efforts have resulted in the
discovery of several potent FTase inhibitors that have
shown efficacy as antitumor agents in human clinical
trials.1
GGTase-I while only about 50 mammalian proteins
are post-translationally modified with farnesyl group.2
Thus, a FTase inhibitor must be selective for FTase over
the closely related enzyme GGTase-I to avoid severe,
nonspecific side effects.3
In our continuing search for novel FTase inhibitors,
compound 1 was identified as a potent and selective
FTase inhibitor (Fig. 1).4 Further modification reveals
that the A-ring of compound 1 can be replaced with a
1-methyl-3-cyano-5-aryl-pyridin-2-one moiety exempli-
fied by compound 2.5 The pyridone-containing com-
pound 2 shows excellent enzymatic activity against
FTase, potent cellular activity, and good selectivity for
FTase over GGTase-I.
CN
CN
N
N
One of the three protein-isoprenyltransferases identified
in mammalian cells is geranylgeranyltransferase type I
(GGTase-I). Both FTase and GGTase-I are hetero-
dimericproteins that share a ocmmon alpha subunit.
Furthermore, FTase and GGTase-I have similar protein
substrate requirements. It has been found that a far
greater number of proteins are the substrates of
N
N
O
O
Cl
N
Cl
A
O
CN
CN
1
2
IC50 0.44 nM (FTase)
2.7 uM (GGTase-I)
EC50 0.5 nM
IC50 0.87 nM (FTase)
1.3 uM (GGTase-I)
EC50 5.2 nM
Keywords: Farnesyltransferase; FTase inhibitor; 1H-pyridin-2-one
derivative.
*
Corresponding author. Tel.: +1-847-9354952; fax: +1-847-
9355165; e-mail: le.wang@abbott.com
Figure 1.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.004

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L. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4603–4606
CN
N
N
O
R
O
Ar
Cl
R:
N
N
R'
O
CN
3
4
Figure 2.
I
Figure 3. ORTEP structure of compound 5c.
I
b
a
N
F
N
F
N
F
8
7
6
Br
Ar
Ar
O
Ar
c
e
O
Ar
d
a
CN
N
N
N
N
9a-c
F
N
N
10a-c
Ar
CN
CN
CN
12a-c
O
b
5a-c
Ar
O
Ar
f
CN
N
N
O
N
CN
5a-c
O
N
H
CN
CN
3a-c
N
OH
13
11a-c
a: Ar=3-chlorophenyl
b: Ar=3,5-dichlorophenyl
c: Ar=3-trifluoromethylphenyl
a: Ar=3-chlorophenyl
b: Ar=3,5-dichlorophenyl
c: Ar=3-trifluoromethylphenyl
Scheme 2. Reagents and conditions: (a) NBS, CCl4, and benzoyl
peroxide; (b) Ag2O, CH2Cl2.
Scheme 1. Reagents and conditions: (a) (1) LDA, THF, À78°C; (2) I2,
À78°C to rt, 74%; (b) (1) LDA, THF, À78°C; (2) H2O, À78°C to rt,
90%; (c) substituted phenylboronic acids, Pd(PPh3)4, 2M Na2CO3,
toluene/EtOH, reflux, 84%; (d) NaCN, DMSO, 110°C, 45%; (e) (1)
H2O2, CH3COOH, 100°C, 6h; (2) Ac2O, reflux overnight; (3) H2O,
dioxane, CH3COONa, reflux 3h, 38% in three steps, (f) MeI, NaH,
DMF, 76%.
anhydride to give the corresponding 2-pyridylacetate.
The 2-pyridylacetates were subsequently hydrolyzed to
give pyridones 11a–c. This three-step sequence usually
gives compound 11 in approximately 30–40% overall
yield from compound 10. N-methylation of compounds
11a–c with MeI and NaH in DMF gave compounds 5a–
c in good yield. Since the general structure of compound
5 had not been reported previously, a singe crystal X-ray
structure of compound 5c was solved to confirm its iden-
tity (Fig. 3).
To further expand our study on the A-ring of compound
1, two new pyridone moieties were investigated (Fig. 2).
In this paper, the synthesis and biological evaluation of
these two series of novel FTase inhibitors are reported.
The preparation of novel heterocycles of the formula
1,5-dimethyl-6-oxo-4-aryl-1,6-dihydro-pyridine-2-carbo-
nitrile 5a–c is reported as well.
Scheme 2 illustrates the synthesis of compounds 3a–c.
Bromination of the methyl group of compounds 5a–c
in CCl4 with NBS and benzoyl peroxide gave compounds
12a–c. Compounds 3a–c were prepared by the coupling
of 12 and 4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-
methyl]-benzonitrile 13 in CH2Cl2 with Ag2O.
The synthesis of compounds 5a–c is shown in Scheme 1.
2-Fluoropyridine 6 was treated with LDA followed by I2
to give compound 7. Compound 8 was prepared
through a method called Ôiodine-dancingÕ by treating
compound 7 with LDA followed by quenching with
H2O.6 The Suzuki coupling of 4-iodopyridine 8 with
various aryl boronic acids gave biaryl compounds 9a–c.
Displacement of the fluorine atom of compounds 9a–c
with a cyano group was achieved by using NaCN in
DMSO to give 2-cyanopyridines 10a–c. The pyridine-
N-oxide of compounds 10a–c, generated by the treat-
ment with H2O2 in acetic acid, was reacted with acetic
Compounds 4a–h were prepared as shown in Scheme 3.
The methyl group of compound 9a was converted to
bromomethyl with NBS and benzoyl peroxide in CCl4.
Coupling of compounds 13 and 14 in CH2Cl2 in the
presence of Ag2O yielded ether 15. Attempts to
hydrolyze the 2-fluoropyridine moiety to give the
corresponding pyridone through methods reported in

L. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4603–4606
4605
when compound 15 was heated in a mixture of acetic
acid and water (9:1) at 100°C over night, the 2-fluoropy-
ridine moiety of compound 15 could be converted to py-
ridone 16 in 90% yield without any breakage of the ether
bond. Finally, N-alkylation of compound 16 was
accomplished with various alkyl bromides in DMF in
the presence of NaH to give compounds 4a–c.
Br
a
Cl
CN
Cl
Cl
N
N
N
N
F
9a
F
14
O
b
CN
N
N
Table 1 illustrates the SAR study on these two pyridone-
containing FTase inhibitors. All of the compounds show
potent activity against FTase and excellent selectivity
for FTase over GGTase-I. It should be noted that,
although compound 3a shows only slightly reduced
activity in the enzymatic assay against FTase compared
to its isomeric counterpart, compound 2, its cell-based
activity is 22-fold less potent than that of compound
2. The reason for this disparity is not clear. Replacement
of the 3-chlorophenyl moiety of compound 3a with a
3,5-dichlorophenyl group (compound 3b) has little im-
pact on the biological activity. However, replacement
of the chlorine with a larger trifluoromethyl group (com-
pound 3c) results in a 6-fold loss in activity against
FTase.
N
F
15
OH
13
CN
CN
N
N
N
N
d
c
O
O
Cl
Cl
HN
N
R
O
O
4
16
Scheme 3. Reagents and conditions: (a) NBS, CCl4, and benzoyl
peroxide; (b) Ag2O, CH2Cl2; (c) acetic acid–H2O (9:1), 100°C, 16h; (d)
alkylbromides, NaH, DMF, 76%.
It appears that a large R group is needed for compound
4 to maintain good activity against FTase since com-
pounds 16 and 4a–b, which bear small substitutents on
literature, such as treatment with 3N HCl at reflux tem-
perature,7 proved to be too harsh for compound 15,
resulting in cleavage of the ether bond. It was found that
Table 1. SAR study for compounds 3a–c, 4a–h, and 16a
IC50 (FTase)b (nM)
IC50 (GGTase)c (nM)
d
EC50 (nM)
Compound
Ar
R
3a
3b
3c
16
4a
4b
3-Cl–Ph
3,5-Di-Cl–Ph
3-CF3–Ph
––
––
1.2 (2)
1.1
7.5
11
>10,000 (2)
9400
3600
11.4 (2)
15
––
H
Nde
Nd
––
––
––
6200
>10,000
>10,000
CH3
CH2CN
12
19
Nd
Nd
N
Br
4c
––
3.0
2.3
6600
Nd
Nd
CN
4d
––
7700
CN
4e
––
1.3 (2)
1900 (2)
9 (2)
NC
4f
––
––
5.0
2.1
>10,000
1200
Nd
10
Cl
4g
F
4h
––
2.1
2000
15
a All the compounds were assayed once unless indicated by the number of the replicates shown in parentheses.
b Compound concentration needed to reduce the bovine FTase-catalyzed incorporation of [3H]FPP into a biotin-linked K-ras (B) decapeptide
(KKSKTKCVIM) by 50%.
c Compound concentration needed to reduce the bovine GGTase-catalyzed incorporation of [3H]FPP into a biotin-linked K-ras (B) decapeptide
(CVLL) by 50%.
d Compound concentration needed to reduce farnesylation of NIH3T3 H-ras transformed cell by 50%.
e Not determined.

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L. Wang et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4603–4606
the nitrogen of the pyridone ring, are less active than
compounds 4c–h. Although compound 4e, which con-
tains a 3-cyanobenzyl group exhibits better activity
against FTase than compound 4f, which contains a 4-cy-
anobenzyl group, the substitution pattern does not seem
to have a large impact on enzymatic activity against
FTase. It is interesting to note that the replacement of
the cyano group of compound 4f with its bioisosteres,
chlorine and fluorine, results in little change in activity
against FTase. However, compound 4e shows slightly
better activity in the whole-cell based assay (EC50) than
compound 4h. The pharmacokinetic properties of com-
pound 4e were studied in dog. At 1mg/kg dose, com-
pound 4e was shown to have 47% oral bioavailability
with 1.4h oral t1/2 and 0.53L/(hkg) plasma clearance.
References and notes
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In conclusion, we have demonstrated that the A-ring of
compound 1 can be replaced with two new pyridone
moieties, leading to two novel series of potent and selec-
tive pyridone-containing FTase inhibitors. In addition
to its potent whole-cell activity, compound 4e was
shown to possess good oral bioavailability in dog. Syn-
thesis of a novel heterocycle, 1,5-dimethyl-6-oxo-4-aryl-
1,6-dihydro-pyridine-2-carbonitrile, was achieved in rea-
sonable yield. The structure of compound 5c was
confirmed by single crystal X-ray structure.
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