Oximino-piperidino-piperidine-based CCR5 antagonists. Part 2: Synthesis, SAR and biological evaluation of symmetrical heteroaryl carboxamides

Article abstract of DOI:10.1016/S0960-894X(02)01063-6

The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and 2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.

Full text of DOI:10.1016/S0960-894X(02)01063-6

Bioorganic & Medicinal Chemistry Letters 13 (2003) 709–712
Oximino-Piperidino-Piperidine-Based CCR5 Antagonists. Part 2:
Synthesis, SAR and Biological Evaluation of Symmetrical
Heteroaryl Carboxamides
Anandan Palani,a,* Sherry Shapiro,a John W. Clader,a William J. Greenlee,a Susan Vice,a
Stuart McCombie,a Kathleen Cox,b Julie Strizkic and Bahige M. Baroudyc
aChemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
bDrug Safety and Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
cAntiviral Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 25 September 2002; accepted 7 November 2002
Abstract—The synthesis, SAR and biological evaluation of symmetrical amide analogues of our clinical candidate SCH 351125 are
described. A series of potent and orally bioavailable CCR5 antagonists containing symmetrical 2,6-dimethyl isonicotinamides and
2, 6-dimethyl pyrimidines amides were generated with enhanced affinity for the CCR5 receptor.
# 2003 Elsevier Science Ltd. All rights reserved.
The process of HIV-1 entry into target cells is an
attractive target for antiviral intervention. One stage in
the HIV-1 entry process that is a particularly plausible
site for pharmacological intervention is the CD4-
dependent interaction between the HIV-1 glycoprotein-
120 complex and the CCR5 chemokine receptor, which
serves as a viral coreceptor.1,2 The CCR5 receptor is a
member of the seven transmembrane G-protein coupled
receptor family, and its natural ligands are the chemo-
kines RANTES, MIP-1a and MIP-1b.3 Individuals who
are homozygous for a 32-base pair deletion in the gene
encoding CCR5, are immunologically normal, and are
strongly protected against HIV-1 infection. Further-
more, heterozygous individuals, who possess only one
intact CCR5, allele advance more slowly to AIDS,
relative to patients having no deletion.4,5 These obser-
vations strongly suggested that inhibiting CCR5 recep-
tor with a small molecule antagonist would provide
protection against HIV-1 infection.
(Sch-C) is a novel and effective agent for the treatment
or prevention of HIV infection.7 In the preceding paper,
we described the physico-chemical properties and bio-
logical evaluation of the rotamers of compound 1.
Although the presence of two restricted bond rotations
present in 1 has no impact on antiviral activity, it cre-
ates significant challenges for development. Therefore,
in order to prepare compounds with a reduced number
of rotamers, we envisioned replacing the unsymmetrical
nicotinamide N-oxide with
a
symmetrical iso-
nicotinamide N-oxide. In this paper, we will describe the
design, synthesis and structure activity studies of
various symmetrical amide analogues of 1.8
We began our studies with the synthesis of 2,6-dimethyl
isonicotinic acid, and the corresponding N-oxide. Start-
ing with commercially available 3,5-lutidine, N-amino-
pyridinium iodide 2 was prepared by treatment with
NH2OSOK and HI (Scheme 1).9a Acylation with acetic
anhydride followed by treatment with amberlite resin
and NaOH yielded 3. Alkylation of 3 with MeI followed
by treatment with KCN provided the 4-cyanopyridine
5.9b Hydrolysis of the nitrile with concentrated HCl
gave carboxylic acid 6, which was allowed to undergo
N-oxidation (H2O2 and AcOH) to afford product 7.
Over the past 2 years numerous publications from our
labs as well as others have appeared describing the anti-
HIV activity of small molecule CCR5 antagonists.6
Recent reports from our laboratories have shown that
the small molecule CCR5 antagonist SCH 351125 (1)
The synthesis of the 2,6-dichloro and the 2,6-dibromo
isonicotinic acid-N-oxides (Scheme 2) started with the
3,5-dihalo pyridines, which were converted to the car-
boxylic acids 8 by treatment with LDA followed by
*Corresponding author. Tel.: +1-908-740-7158; fax: +1-908-740-
7305; e-mail: anandan.palani@spcorp.com
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(02)01063-6

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A. Palani et al. / Bioorg. Med. Chem. Lett. 13 (2003) 709–712
solid CO2.10 The nicotinic acids 8 were then oxidized to
the N-oxides 9 by treatment with m-CPBA.
the enol ether 13 by generation of the cesium salt fol-
lowed by subsequent quenching with methyl triflate.11a
No evidence of C-alkylation was observed although
starting material was recovered. Condensation of 13
with various amidines generated the desired heterocyclic
The carboxylic acids 7 and 9 were then coupled under
standard conditions with the piperidino-piperidine core
10, synthesized using the method described previously,
7b to afford the targets 11a–11f (Scheme 3).
Table 1. SAR and pharmacokinetic properties of 2,6-disubstituted
isonicotinic amides
Analogues 11a, 11c and 11e as shown in Table 1 are
very potent CCR5 antagonists, with IC50 values less
than or equal to 1 nM. The oral plasma levels observed
in rats were 2–10-fold lower for the nicotinamides than
for the corresponding N-oxides, which is expected from
our previous studies showing that the nicotinamides are
readily oxidized to the N-oxides in vivo.7b The symme-
trical N-oxides (11b, 11d and 11f) also provided potent
CCR5 antagonists which are comparable to our lead
antagonist 1. After oral administration to rats, the pyr-
idine N-oxides achieved plasma levels higher than those
for the corresponding pyridines, but still lower than
those for 1.
d
Ki (nM)a,b IC50 (nM)c Rat PK (10 mg/kg po)
.
Ar
AUC0À6 h (h mg/mL)
1
2.1
2.3
0.6
6.5
1.3
11a
Next, we investigated symmetrically substituted pyr-
imidines as replacements for the nicotinamide-N-oxide
in 1. The synthesis of the substituted pyrimidines is
outlined in Scheme 4. The diketone 12 was converted to
11b
11c
8.8
0.4
0.40
0.69
1.6
0.5
11d
11e
11f
1.2
0.3
0.7
0.15
1.04
1.24
3.9
0.5
4.4
Scheme 1. Synthesis of 2,6-dimethyl isonicotinamides.
aData for the inhibition of RANTES binding and 23 ꢀC for 60 min.
bThe standard error was 10% and variability was 2–3-fold from assay
to assay.
cConcentration required to inhibit by 50% the entry of HIV-1 repor-
ted virus (ADA) into U-87 cells; see ref 7c for assay procedures. For
IC50 values, 95% confidence limit was within 1 log and intraassay
variation less than 0.5 log.
dSee ref 12 for procedure.
Scheme 2. Synthesis of 2,6-disubstituted isonicotinamides.
Scheme 3. Synthesis of symmetrical amide analogues of 1.

A. Palani et al. / Bioorg. Med. Chem. Lett. 13 (2003) 709–712
711
Table 3. SAR and pharmacokinetic properties of 2-substituted-4,6-
dimethyl pyrimidine amides
Scheme 4. Synthesis of substituted pyrimidines.
d
.
Rat PK (10 mg/kg po)
AUC0À6 h (h mg/mL)
Ar
Ki
IC50
(nM)a,b (nM)c
1
2.1
2.2
0.6
6.5
Table 2. SAR and pharmacokinetic properties of compounds with a
4,6-dimethyl pyrimidine amide
16b
0.36
3.1
17a
17b
17c
17d
17e
17f
17g
2.1
3.2
5.7
0.93
0.26
0.35
2.7
2.0
3.1
d
.
R2
Ki (nM)a,b IC50 (nM)c Rat PK (10 mg/kg po)
AUC0À6 h (h mg/mL)
1
2.1
4.7
2.2
2.0
14
8.1
11
3.3
0.6
6.5
4.1
3.1
1.6
6.9
16a
16b
16c
16d
Me
Et
Pr
1.83
0.36
0.89
3.80
16e
16f
16g
1.17
0.6
3.7
2.4
60
iPr
0.28
315
43
aData for the inhibition of RANTES binding and 23 ꢀC for 60 min.
bThe standard error was 10% and variability was 2-3 fold from assay
to assay.
cConcentration required to inhibit by 50% the entry of HIV-1 repor-
ted virus (ADA) into U-87 cells. see ref 7c for assay procedures. For
IC50 values, 95% confidence limit was within 1 log and intraassay
variation less than 0.5 log.
dSee ref 12 for procedure.
25
esters 14 in 11–60% yield.11b Hydrolysis followed by
acidification gave the desired acids 15 in quantitative
yield.
17h
17i
5.3
0.13
1.8
0.4
The pyrimidine acids 15 were then coupled with amine
10 under standard conditions. The biological data for
the resulting amides are summarized in Tables 2 and 3.
These amides showed receptor binding profiles similar
to those of the nicotinic acid N-oxide amides;7b com-
pounds with small O-alkyl substituents on the oxime
(16b) and (16c) were optimal. These antagonists showed
CCR5 binding affinity simillar to that of our lead
antagonist 1 and also gave comparable plasma levels in
rats following oral administration.
1.3
aData for the inhibition of RANTES binding and 23 ꢀC for 60 min.
bThe standard error was 10% and variability was 2–3 fold from assay
to assay.
cConcentration required to inhibit by 50% the entry of HIV-1 repor-
ted virus (ADA) into U-87 cells; see ref 7c for assay procedures. For
IC50 values, 95% confidence limit was within 1 log and intraassay
variation less than 0.5 log.
In order to address potential metabolism at the 2-posi-
tion of the pyrimidine moiety, as well as to improve the
dSee ref 12 for procedure.

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A. Palani et al. / Bioorg. Med. Chem. Lett. 13 (2003) 709–712
overall profile, several 2-substituted 4,6-dimethyl 5-pyr-
imidine carboxylic acid derivatives were prepared. Small
alkyl groups at the 2-position of pyrimidine are toler-
ated. For example, compounds with methyl (17a), tri-
fluoromethyl (17b), methoxy (17h) substituents
exhibited good CCR5 binding affinity. 2-Amino sub-
stitution as in 17c was also acceptable, but amido
and sulfonamido pyrimidines (17d, 17e) were found to
be less active. Clearly, analogues with substitution at
the 2-position provided no improvement in overall
pharmacokinetic profile.
References and Notes
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The inhibition of binding at the CCR5 receptor corre-
lated well with inhibition of viral entry for both pyr-
imidine and isonicotinic N-oxide analogues of 1. In both
series, in general methoxime analogues are less potent in
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YU-2 in U-87 cells with IC50 values less than 1 nM.
Furthermore, compounds 16a and 16b inhibited the
replication of a primary HIV-1 isolate (US-1) in PBMCs
with IC50 values comparable to that of antagonist 1
(IC50=2.6 nM for 16a).7b,7c Despite meeting all the cri-
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liability of 16a was a lack of consistent antiviral activity
against a wide range of genetically diverse HIV-1 iso-
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oxide moiety in the lead antagonist 1. Symmetrical pyr-
imidines, 2-substituted pyrimidines and 2,6-dis-
ubstituted isonicotinamides and their corresponding N-
oxides are all well tolerated, providing potent CCR5
receptor antagonists with comparable efficacy in both
binding and viral entry assays to our lead antagonist 1,
while reducing the number of rotational isomers. Our
continuing efforts to improve the overall profile of these
compounds will be published in due course.
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Acknowledgements
We thank Drs. Jayaram Tagat, Michael Miller and
Bernard Neustadt for many useful discussions. Drs.
Ashit Ganguly, John Piwinski and Gregory Reyes are
acknowledged for their support and encouragement.