Trifluoromethyl-containing 3-alkoxymethyl- and 3-aryloxymethyl-2-pyridinones are potent inhibitors of HIV-1 non-nucleoside reverse transcriptase

Article abstract of DOI:10.1016/S0960-894X(00)00662-4

3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the most potent compound 24 exhibiting an IC₉₀ = 32 nM. Compound 24 also possessed a potent resistance profile as demonstrated by submicromolar IC₉₀s against several clinically meaningful mutant virus strains.

Full text of DOI:10.1016/S0960-894X(00)00662-4

Bioorganic & Medicinal Chemistry Letters 11 (2001) 309±312
Tri¯uoromethyl-Containing 3-Alkoxymethyl- and
3-Aryloxymethyl-2-pyridinones Are Potent Inhibitors of HIV-1
Non-Nucleoside Reverse Transcriptase
Je€rey W. Corbett,* Kristen J. Kresge, Senliang Pan, Beverly C. Cordova,
Ronald M. Klabe, James D. Rodgers and Susan K. Erickson-Viitanen
DuPont Pharmaceuticals Company, Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, USA
Received 6 September 2000; accepted 10 November 2000
AbstractÐ3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside
reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the
most potent compound 24 exhibiting an IC90=32 nM. Compound 24 also possessed a potent resistance pro®le as demonstrated
by submicromolar IC90s against several clinically meaningful mutant virus strains. # 2001 DuPont Pharmaceuticals Company.
Published by Elsevier Science Ltd. All rights reserved.
The emergence of mutant forms of HIV-1 in both
treatment-experienced and increasingly in treatment-
naõve patients underscores the necessity to continue to
develop e€ective, well-tolerated treatments for this dis-
ease. Previous work has shown 3-aminoalkyl- and 3-
alkyl-2-pyridinones to be active inhibitors of HIV-1
RT.1,2 Unfortunately, resistant strains of HIV-1 rapidly
developed in vivo when 3-aminoalkyl-2-pyridinones
were advanced into clinical trials and administered as
either monotherapy or in combination with zidovu-
dine.3,4 As part of a continuing e€ort in these labs to
develop NNRTIs that have a virologic pro®le sucient
to inhibit wild-type and mutant viral types and possess
pharmacokinetics consistent with once-daily dosing, the
hybrid 2-pyridinones containing tri¯uoromethyl and
cyclopropyl alkynyl groups were investigated (Fig. 1).5 7
The incorporation of these functional groups has
improved resistance pro®les in quinazolinones, as
demonstrated by DPC961 and DPC083, and are incorpo-
rated in the marketed NNRTI SUSTIVA TM (efavirenz).5
anion with ethyl tri¯uoroacetate to cleanly a€ord tri-
¯uoromethyl ketone 2.8 It proved critical to use the
hindered mesityl lithium base when metallating 1 to
eliminate the production of alkylated side products.
Employing the mesityl lithium metallation procedure to
2-methoxyquinoline (3) resulted in the isolation of hemi-
ketal 4, with no ketone being present. Compound 4 was
used as is in subsequent alkylation reactions. 5-Ethyl-3-
formyl-6-methyl-2-methoxypyridine 5 was prepared as
The synthesis of the target pyridinones in Figure 1
required the preparation of the tri¯uoromethyl ketones
shown in Scheme 1. 2-Methoxypyridine (1) was metal-
lated with mesityl lithium followed by quenching the
*Corresponding author at current address: Pharmacia, 7255-209-643,
301 Henrietta St., Kalamazoo, MI 49007-4940, USA. Fax: +1-616-
833-1559; e-mail: je€rey.w.corbett@am.pnu.com
Figure 1. Design of tri¯uoromethyl-containing pyridinones.
0960-894X/01/$ - see front matter # 2001 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00662-4

310
J. W. Corbett et al. / Bioorg. Med. Chem. Lett. 11 (2001) 309±312
previously described in the literature.1c To 5 was added
trimethyl(tri¯uoromethyl)silane and tetrabutylammonium
¯uoride (TBAF) to give the secondary alcohol which
was subsequently oxidized with the Dess±Martin peri-
odinane reagent to a€ord ketone 6.9
was 9 times more active in the enzyme assay and 4 times
more active in the whole cell assay (Table 1). It was also
found that the size of the R4 group is critical for activ-
ity. In comparing 22±27, a trend becomes apparent
wherein compounds with a hydrophobic R4 group of at
least three carbons are the most active compounds.
Replacing the methyl and ethyl groups with an aromatic
ring a€orded quinolinone 21, which was approximately
10 times less active in the whole cell assay than pyr-
idinone 27. Also, the compound that had a phenyl
group at R3 (20) was less potent than the
corresponding analogue with a cyclopropyl group (15).
Treating 2, 4, and 6 with an excess of lithiated alkynes
in THF a€orded tertiary alcohols 7a±c as shown in
Scheme 2 (see Table 1 for de®nitions of R3 and R4). The
alcohols were then alkylated with various alkyl halides
to yield ethers 8a±c. When sodium methiolate was used
to deprotect 8a, the only material isolated was 9 in
which the pyridinone oxygen cyclized onto the alkyne.
The best conditions found for removal of the methyl
ether from 8a±c utilized trimethylsilyl iodide (TMSI) in
methylene chloride at re¯ux.
The incorporation of a trans-ole®n into quinazolinones
DPC961 and DPC963 led to compounds that exhibited
unique virologic and pharmacokinetic properties.5
However in the tri¯uoromethyl-containing pyridinones,
an unexpected decrease in the biological activity, as
demonstrated in the whole cell assay, was observed. For
instance, trans-ole®n 13 and the corresponding alkyne
15 had enzyme IC50s of >1400 nM and 182 nM,
respectively. The divergence in the SAR between the
pyridinones and the quinazolinones implies that at least
the ole®n containing pyridinones are binding in a di€er-
ent orientation than the ole®n-containing quinazolinones
DPC082 and DPC083.5
Other attempts were made to prepare pyridinones
wherein R4 was either a benzimidazole or benzoxazole
(Scheme 3). In the event, treating 7c with 2-(bromo-
methyl)benzimidazole10 or (2-bromo-methyl)benzox-
azole11 a€orded the desired ethers 10a,b. Unfortunately,
all attempts to deprotect 10a,b using TMSI led to the
exclusive formation of the pyrano[2,3-b]pyridines 11a,b.
The structure of 11a was con®rmed through a single
crystal X-ray structure. It remains unclear why com-
pounds possessing the benzimidazole or benzoxazole
groups undergo an intramolecular cyclization while a
benzyl group in the same position does not induce a
similar reaction. Attempts at preparing alternately pro-
tected pyridines were pursued without success. Com-
pounds 9 and 11a,b were found to not possess any
activity in the enzyme and antiviral whole cell assays.
The K103N mutation has been designated as a `pan-
class' mutation since it is frequently observed in patients
failing an NNRTI-containing therapy.7 Following the
appearance of the K103N mutation, double mutant
viruses containing the K103N mutation occur with the
K103N/P225H and K103N/V108I mutations more
common than the K103N/L100I mutation. Since a ser-
ies of compounds predicted to provide inhibition of the
To explore the steric environment surrounding the
alkynyl group, two alkynes 7a (R3=cyclopropyl or
phenyl) were reduced with lithium aluminum hydride to
a€ord trans-ole®ns 12 (Scheme 4). Alkylation of the
tertiary alcohol with benzyl bromide and removal of the
methyl ether with TMSI delivered ole®ns 13 and 14,
respectively. All of the compounds prepared via
Schemes 2 and 4 for which biological data were
obtained are listed in Table 1.12
The importance of the R1 and R2 substituents became
evident when pyridinone 27 was compared to pyr-
idinone 15, which lacks the methyl and ethyl groups: 27
Scheme 1. Synthesis of 2-methoxypyridyl and 2-methoxyquinoline
tri¯uoromethyl ketones.
Scheme 2. Synthesis of tri¯uoromethyl-containing pyridinones.

J. W. Corbett et al. / Bioorg. Med. Chem. Lett. 11 (2001) 309±312
311
K103N, K103N/P225H, and K103N/V108I mutants
were selected for further development,5,7 our attention
focused upon identifying agents capable of inhibiting
the K103N/L100I mutant while maintaining activity
against other single and double mutant viral forms.
Therefore, compounds 24 and 27 were evaluated for
activity against clinically important mutant strains of
HIV-1 (Table 2).12
L697,661.13 Pyridinone 27 su€ered a signi®cant loss in
activity against the K103N/V108I mutant and was less
potent against this mutant when compared to the qui-
nazolinones and efavirenz. However, 27 possessed sig-
ni®cant activity against virus containing the K103N/
P225H mutation: 27 was at least as potent as efavirenz
and possibly DPC083. Finally, 27 was signi®cantly
more potent than efavirenz and marginally better than
the quinazolinones DPC961 and DPC083 at inhibiting
the K103N/L100I double mutant virus.
The quinazolinones DPC961 and DPC083 were more
potent than 24, 27 and efavirenz at inhibiting the
K103N single mutant virus than Table 2. Since the
values in Table 2 for 24 and 27 are for the racemates,
and the single enantiomers are typically twice as active
as the racemates, one would anticipate that enantio-
meric 24 and 27 would be as active against K103N as
efavirenz.5,6 Pyridinones 24 and 27 were also sig-
ni®cantly more potent against the K103N mutant than
In summary, a series of potent tri¯uoromethyl-contain-
ing pyridinone NNRTIs was discovered that possess
nanomolar activity toward wild-type virus and, more
importantly, had a good resistance pro®le toward the
K103N/L100I and K103N/P225H double mutants. In
fact, 27 was more potent against the K103N/L100I
double mutant than DPC961, DPC083 and efavirenz.
Table 1. Structure and biological activity of compounds.12 See Schemes 2 and 4 for generic structures containing R1, R2, R3, and R4
Compound
R1
R2
R3
R4
Alkyne/ole®n
Enzyme assay IC50 (nM)
Whole cell assay IC90 (nM)
Efavirenz
47 (Æ25)
31 (Æ8)
19 (Æ4)a
16,676
43,894
11,824
25,999
25,564
8115
24,338
1.7 (Æ0.5)
2.0 (Æ0.7)
50±100b
>1400
>1300
182
1006
>1435
431
>1140
>1300
579
201
95
DPC961
L697,661
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
cycPr
Phenyl
cycPr
cycPr
cycPr
cycPr
cycPr
Phenyl
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
cycPr
Benzyl
Benzyl
Benzyl
Ole®n
Ole®n
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
Alkyne
2-Pyridylmethyl
3-Pyridylmethyl
4-Pyridylmethyl
Ph-3-(OPhenyl)
Benzyl
11,691
36,008
770
CHˆCHCHˆCH
Benzyl
Methyl
Ethyl
Propyl
CH2cycPr
Butyl
Benzyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
183 (Æ71)
105 (Æ38)
188 (Æ34)
129 (Æ38)
1348 (Æ271)
613 (Æ270)
6093
32
37
42
46
49
61
157
160
2,6-diF-benzyl
2-Cl, 6-F-benzyl
2,6-diCl-benzyl
2-F, 6-MeOBenzyl
2,4-diCl-Benzyl
3,5-diMeO
CH2CN
41,102
1951 (Æ457)
2696 (Æ2111)
3843 (Æ2014)
1842
190
579
1400
aThe assay conditions used to determine the enzyme IC50 for L697,661 reported in ref 1d are di€erent from the conditions used in our enzyme assay.
bThe value reported in ref 1g is the CIC95, not the IC90
.
Scheme 4. Preparation of ole®ns 13 and 14.
Scheme 3. Formation of 4H-pyrano[2,3-b]pyridines.

312
J. W. Corbett et al. / Bioorg. Med. Chem. Lett. 11 (2001) 309±312
Table 2. Resistance pro®le of pyridinones 24 and 27
Efavirenz
DPC961
DPC083
L697661
24
27
K103N IC90 (nM)
64 (Æ24)a
240 (Æ68)a
7300 (Æ5000)a
10 (Æ3.2)a
38 (Æ4)a
1100 (Æ160)a
27 (Æ11)a
90 (Æ6.6)a
800b
nd
nd
nd
144
nd
nd
nd
113
1207
283
K103N/V108I IC90 (nM)
K103N/P225H IC90 (nM)
K103N/L100I IC90 (nM)
310 (Æ130)a
73 (Æ18)a
140 (Æ92)a
1690 (Æ160)a
668
aValues are means of three experiments, standard deviation is given in parentheses.
bThe value reported is the CIC95 from ref 13. No data=nd.
Compounds 24 and 27 were also more potent against
the K103N single mutant than previously reported pyr-
idinones, including L697,661.13 E€orts to expand on the
SAR of this new series of NNRTIs will be reported in
due course.
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