Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication

Article abstract of DOI:10.1016/j.bmcl.2011.09.133

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.

Full text of DOI:10.1016/j.bmcl.2011.09.133

Bioorganic & Medicinal Chemistry Letters 21 (2011) 6950–6954
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Bioorganic & Medicinal Chemistry Letters
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Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide
CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication
Renato Skerlj a, , Gary Bridger b, Yuanxi Zhou b, Elyse Bourque a, Ernest McEachern b, Jonathan Langille b,
⇑
Curtis Harwig b, Duane Veale b, Wen Yang b, Tongshong Li b, Yongbao Zhu b, Michael Bey b, Ian Baird b,
Michael Sartori b, Markus Metz a, Renee Mosi b, Kim Nelson b, Veronique Bodart b, Rebecca Wong b,
Simon Fricker a, Ron Mac Farland b, Dana Huskens c, Dominique Schols c
a Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA
b AnorMED Inc., 200-20353 64th Avenue, Langley, British Columbia, Canada V2Y 1N5
c Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral
blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma
Received 22 August 2011
Revised 29 September 2011
Accepted 30 September 2011
Available online 8 October 2011
protein binding, potency shift in the presence of
pharmacokinetics.
a
-glycoprotein were evaluated in rat and dog
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
CCR5
Chemokine receptor
HIV-1
Schering C
The importance of CCR5 and CXCR4 as co-receptors for HIV-1 has
been well established.1 During the last decade numerous research
groups2 have endeavored to develop small molecule inhibitors of
CCR5 to treat M tropic (R5) HIV-1 infection, and although groups
have faced significant development hurdles, Pfizer was ultimately
successful in gaining FDA marketing approval for maraviroc3 in
2007. Our group was the first to demonstrate viral load reduction
in T tropic (X4) HIV-1 infected patients by specifically blocking
CXCR4 with small molecule antagonists AMD31004 and AMD070.5
Plerixafor (AMD3100) was eventually approved in 2008 in the U.S.
for use in combination with granulocyte colony-forming factor to
mobilize hematopoietic stem cells for autologous transplantation
in patients with non-Hodgkin’s lymphoma (NHL)6 and multiple
myeloma (MM).7 However, since the treatment of dual/mixed tro-
pic HIV-1 infection would likely require the combination of a CXCR4
and a CCR5 antagonist we also initiated a research effort to find
small molecule antagonists of CCR5.
(BaL) replication in PBMC. These compounds were identified by
the re-design of Schering C9 (1) (Fig. 1) and during this research
effort a second aniline series8 was also identified which is the
subject of this Letter. Our interest in pursuing the second series
EtO
N
N
Br
1
Schering C ( )
N
N+
O-
O
R1
X
N
N
2, X=C
H
N
N
R2
3
, X=N
R
R
O
Recently we reported8 on the identification of pyridin-2-ylo-
xymethylpiperidin-1-ylbutyl amides (O-aryl series) as a novel class
of CCR5 antagonists that exhibited potent inhibition of R5 HIV-1
N
N
4, R=OMe
H
N
R2
5
O
⇑
Corresponding author. Tel.: +1 781 434 3684; fax: +1 781 672 5823.
E-mail address: renato.skerlj@genzyme.com (R. Skerlj).
Figure 1. Structure of Schering C (1) and related analogs 2–5.
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.09.133

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6950–6954
6951
Table 1
Fusion binding inhibition, anti-HIV-1 activity and cellular cytotoxicity of compounds 2a
R1
Cl
N
N
N
H
N
R
O
Cl
M)
b
c
d
Compd
R
R1
Fusion IC50
(
l
HIV-1 IC50
(l
M)
CC50 (lM)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
Br
CF3
H
H
H
H
H
H
H
H
0.049 (n = 2)
0.034 (n = 3)
0.050 (n = 3)
0.026 (n = 2)
0.019 (n = 2)
0.090 (n = 2)
0.116 (n = 2)
0.011 (n = 84)
na
0.030 (n = 2)
na
0.22 (n = 2)
0.11 (n = 2)
2.17
0.059
0.38 (n = 2)
0.177
9.633
0.096 (n = 4)
> 1.25
0.40
>1.30
2.88
0.089
0.001 (n = 2)
0.014 (n = n = 4)
0.002
4.3
8.1
36.5
4.0
9.7
OMe
OCF3
CN
CO2Me
CONMe2
OPhCO2H
Br
Br
Br
Br
Br
21.4
>30.0
22.1
5.7
7.3
4.3
6.4
6.7
12.3
>1.76
6.0
2-Cl
3-Cl
4-Cl
3-OMe
3-CN
3-CN
3-CN
3-CN
3-CN
0.387
0.008 (n = 3)
0.003 (n = 5)
0.002 (n = 49)
0.003 (n = 5)
0.012 (n = 3)
CF3
OMe
OCF3
CN
0.376
33.6
a
Assays were performed in duplicate and values represent the mean with standard deviations <30% of the mean. Bracketed values represent the number of experiments.
Viral gp120/CCR5 binding was assessed by a cell fusion assay between P4R5 cells expressing CCR5, CD4 and a LTR-b-gal construct (LacZ gene under the control of the HIV-
b
1 LTR promoter) and CHO-tat cells expressing the HIV-1 JRFLenv and HIV-1 Tat. The P4R5/CHO-tat, CCR5/gp120 interaction was assessed by measuring the resultant b-
galactosidase activity. IC50 is the concentration of compound required to inhibit cell fusion by 50%.
c
Peripheral blood mononuclear cells (PBMC) were isolated from healthy volunteers and infected by R5 HIV-1 (BaL strain) as reported in Ref..10. IC50 is the concentration of
the compound required to inhibit viral replication by 50% as measured by p-24 HIV-1 specific Ag ELISA.
d
CC50 is the concentration required to reduce the viability of PBMC by 50%.
was to improve upon the poor pharmacokinetic properties exhib-
ited by the O-aryl series. The antiviral activity was used to deter-
mine a structure–activity-relationship (SAR) and it was measured
utilizing the R5 HIV-1 PBMC assay. In addition we also utilized
the fusion binding assay10 as a first pass screen to select com-
pounds for anti-viral screening since the fusion data was found
to be a reliable predictor of anti-viral activity.
Compound 2a (Table 1), representing the aniline series, was
identified during our initial efforts to find a replacement for the
oxime moiety of Schering C.8 During the SAR development of the
O-aryl series we determined that an electron withdrawing substi-
tuent at the corresponding 3-position of the aryl ring enhanced
antiviral potency and indeed this SAR was found to be applicable
to compounds 2. For example, the 3-CN analog 2m was approxi-
substituted aniline 6 with N-(t-butoxycarbonyl)-piperidin-4-one
followed by N-alkylation with a substituted benzyl halide to afford
the intermediates 7 in good overall yield (Scheme 1). Elaboration
to compounds 2a–2q was accomplished using methodology previ-
ously reported.8 Although compounds 2h and 2p had good rat and
dog PK (Table 4) these compounds, comparable to others in the
series, had high plasma protein binding (>99.9%) and marginal
physicochemical properties (solubility). Our strategy to improve
the properties of these compounds while still maintaining potent
anti-HIV-1 activity was to substitute the R1-phenyl ring with het-
erocyclic rings and investigate modification of the dichloropyridine
group with more hydrophilic moieties to reduce liphohilicity. Sev-
eral heterocyclic replacements for the R1-phenyl ring were synthe-
sized including, furan, oxazole, thiazole, imidazole and pyrazine
but the pyridine and thiophene rings were the most promising
based on antiviral potency. As a consequence the pyridine com-
pounds provide the basis for the ongoing discussion.
mately three-fold more potent then 2a with an IC50 of 0.089
lM
versus 0.22 M in the HIV-1 assay. As was the case in the O-aryl
l
series when R was a CF3 (2b) or OCF3 (2d) substituent a moderate
enhancement in antiviral activity was observed. However, when
these groups were combined with the 3-CN substituent (R1), ana-
logs 2n and 2p, the antiviral potency was dramatically increased,
The position at which the pyridine ring was attached was
important regarding antiviral activity and the compounds in Table
2 represent the pyridine series linked at the 3-position. Lipohilicity
was assessed by calculating the clogP and the potential in vivo sig-
nificance was determined by calculating the potency shift in the
IC50 of 0.001 and 0.002
the more hydrophilic OMe group 2o the anti-HIV-1 potency was
0.014 M compared to the unsubstituted analog 2c which was
2.17 M. Extending the size of the R group with a 4-phenoxyacid
lM, respectively. Moreover, even with
l
l
presence of a-glycoprotein (AGP) and the human plasma protein
binding. The SAR was based on the R enantiomer since early on
we established that the R enantiomer was substantially more po-
tent both in the fusion binding assay and the anti-HIV-1 assay.
For example, the fusion binding IC50 difference between the two
enantiomers 4f and 4h was 200-fold, 0.2 nM versus 40 nM, respec-
tively. It was also found that substitution of the pyridine ring with
a methyl group at the 4-position provided an approximate 10-fold
increase in potency which was confirmed by several analogs. For
example, comparison of the methyl analogs, 4f and 4i, to the cor-
responding des methyl analogs, 4g and 4j, showed anti-HIV-1
IC50s of 2.2 nM versus 18.9 and 29.6 nM. Since the 4-Me substitu-
ent provided an enhancement in HIV-1 potency we utilized this
moiety 2h resulted in comparable potency to 2d. The compounds
were synthesized by reductive amination of the appropriately
R1
NH2
N
a-c
ref 5
2a-2q
NH
R
R
6
7
Scheme 1. Reagents and conditions: (a) NaBH(OAc)3, N-(t-butoxycarbonyl)-piper-
idin-4-one, AcOH, 1,2-dichloroethane, 60%; (b) RX, KI, K2CO3, CH3CN, 65 °C, 80%; (c)
TFA, CH2Cl2, rt, 100%.

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R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6950–6954
Table 2
Fusion binding inhibition, anti-HIV-1 activity, cellular cytotoxicity and protein binding of compounds 4a
R1
N
N
H
N
N
R2
MeO
O
Compd
R1
R2
MW/clogP
CCR5 fusion IC50 (nM)
Fold IC50 protein shiftb
10.6
HIV-1 PBMC IC50 (nM)
PBMC CC50 (nM)
>38300
Protein bindingc (%)
75
N
4a
Me
517/3.3
10.9 (n = 10)
1830 (n = 2)
N
N
4b
4c
Me
Me
516/4.1
516/4.1
7.0 (n = 4)
12.6
9.4
11479
>38800
>38900
na
95
2.4 (n = 10)
1044 (n = 2)
N
N
4d
Me
536/3.9
0.7
9.0
22.3 (n = 3)
>37700
88
Cl
Cl
Cl
4e
4f
Me
Me
536/4.8
550/4.9
12.3
na
na
na
na
92
N
N
0.2 (n = 8)
8.7
2.2 (n = 5)
>36400
Cl
Cl
F
4g
H
536/4.5
550/4.9
534/4.4
536/3.9
541/3.9
1.5 (n = 3)
40
3.9
na
18.9
>37300
na
93
na
79
86
98
N
N
N
N
N
(S)-4h
4i
Me
Me
H
na
0.3 (n = 7)
1.6 (n = 4)
0.3 (n = 3)
7.7
3.8
8.6
2.2 (n = 3)
29.6 (n = 2)
25.4 (n = 3)
>36300
>36700
>34800
F
4j
CN
O
4k
Me
NH
4l
Me
600/4.9
0.09 (n = 7)
6.0
0.96 (n = 2)
>32800
89
N
a
b
c
See footnotes in Table 1.
Fold IC50 protein shift is the shift in the CCR5 fusion assay in the presence of 1 mg/mL of
Plasma protein binding was calculated by diluting a 25 mM stock solution in DMSO to 1
a
-acid glycoprotein.
lM in human plasma, dialyzing for 5 h against PBS (pH 7.4) at 37 °C and
determining the concentration remaining in each compartment by LC–MS/MS analysis.
substituent for modification of the dichloropyridine amide. Use of a
dimethylpyrimidine moiety 4a successfully reduced the clog P to
3.3 but had a deleterious effect on anti-HIV-1 potency (IC50 of
was 25.4 nM. Interestingly substitution with the amide 4l provided
the most potent antiviral analog, IC50 of 0.96 nM. Analogs 4f, 4i and
4l had acceptable human plasma protein binding in the range of
79–92% and an acceptable fold AGP fusion shift in the range of
6–9. These compounds, in addition to 4d, were also profiled in
rat and dog PK (Table 4). Based on an oral bioavailability of at least
20% in both species and consideration of potency and other in vitro
properties described above compound 4f had the best overall
profile.
The 6-chloro and 6-cyano pyridine amide precursors were
synthesized from commercially available ethyl 2,4-dimethylnicoti-
noate (Scheme 2) via nucleophilic addition to the corresponding
N-oxide. For example, reaction with POCl3 followed by ester
hydrolysis afforded the chloride 9 in good yield whereas reaction
with TMSCN gave the nitrile 8. The 6-fluoro amide precursor was
synthesized from the diazonium salt of 5-bromo-4,6-dimethylpyri-
din-2-amine followed by nucleophilic displacement with fluoride to
afford intermediate 10. Lithiation of the bromide 10 with t-BuLi fol-
lowed by trapping with CO2 gave the acid 11. The chiral iso-butyl
1.8 lM). Replacement with the corresponding dimethylpyridine
group 4c, although more lipophilic, did improve the fusion binding
5-fold but had a marginal effect on anti-HIV-1 activity. However,
4c was 10-fold more active then the regioisomer 4b confirming
that the optimum point of attachment was at the 3-position. Inter-
estingly, the simple substitution of a chlorine atom at the 2-posi-
tion 4d resulted in a 47-fold enhancement in anti-HIV-1 potency,
IC50 of 22 versus 1044 nM. It was apparent that slight modification
of the amide pyridine ring had a profound impact on potency. For
instance, merely changing the chlorine from the 2-position 4d to
the 6-position 4e resulted in an approximate 20-fold loss in fusion
binding. But perhaps even more surprising was that the addition of
a methyl group to the 2-position 4f resulted in a 60-fold increase in
fusion binding and a comparable gain in anti-HIV-1 potency, IC50 of
2.2 nM. Similarly, the antiviral potency of the 6-F analog 4i was
2.2 nM. Although the fusion binding of the nitrile 4k was compara-
ble to the chloro 4f and fluoro 4j analogs the anti-viral activity IC50
linker was readily prepared from commercially available D-alanine

R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6950–6954
6953
Table 3
Fusion binding inhibition, anti-HIV-1 activity, cellular cytotoxicity and protein binding of compounds 5 and 3a
N
R1
N
N
N
H
N
H
N
R2
N
R2
N
R
R
O
O
3
5
Compd
R
R1
R2
MW/
clogP
CCR5 Fusion IC50
(nM)
Fold IC50 protein
shift
HIV-1 PBMC IC50
(nM)
PBMC CC50
(nM)
Protein binding
(%)
Cl
CN
F
5a
5b
5c
5d
5e
5f
O(CH2)2OMe
O(CH2)2OMe
O(CH2)2OMe
SOMe
594/4.4
0.6 (n = 6)
0.8 (n = 5)
1.3 (n = 4)
130
3.2
1.5
2.3
na
2.0 (n = 3)
32.3 (n = 3)
23.1 (n = 2)
>32149
3.3 (n = 3)
na
>32700
>32600
>32700
>32400
>34300
na
85
92
81
na
89
94
na
91
84
79
N
N
N
585/3.8
578/4.2
549/2.3
583/2.6
511/4.0
529/1.0
552/3.3
561/4.3
545/3.7
N
N
N
N
N
N
N
N
CN
CN
Cl
OCH2CONH2
H
0.98 (n = 5)
7.0 (n = 2)
1586
1.2
2.6
na
N
O
5g
3a
3b
3c
na
na
CN
Cl
OMe
OMe
OMe
CN
CN
CN
0.3 (n = 6)
0.3 (n = 5)
0.7 (n = 5)
4.4
2.4
3.0
3.9 (n = 3)
3.5
>36300
>35100
>35800
F
3.6 (n = 3)
a
See footnotes in Table 1 and Table 2.
methyl ester which after reduction and Boc protection gave (R)-tert-
butyl(1-hydroxypropan-2-yl)carbamate 12. A series of functional
group interconversions gave the nitrile 13, which was treated with
1-ethylmethyl-4-piperidone iodide11 to afford the key intermediate
14 in 99% enantiomeric excess. The compounds in Tables 2 and 3
were prepared using 14 as exemplified by the preparation of
compound 4f. Reductive amination with 4-methoxyaniline afforded
the corresponding amine 15 which was coupled with 4-
methylnicotinyl chloride to install the right hand side pyridine
amide. Borane reduction of the nitrile to the amine 16 followed
Table 4
Pharmacokinetics of 2h, 2p, 3b, 4d, 4f–g, 4i, 4l and 5a in rat and doga
Compd
Species
Cmax
M)
AUC0–
CL
(ml/min/
kg)
V
(L/
kg)
T1/2
(h)
F
(%)
(
l
inf
(h⁄lM)
2h
2p
4d
4f
4g
4i
Rat
2.79
0.53
3.11
3.80
1.33
1.27
1.07
9.07
7.30
18.3
22.7
4.83
10.88
7.18
30.0
131.7
58.7
46.7
20.6
16.6
61.2
4.2
4.8
5.0
3.0
10.0
8.6
3.3
1.7
16
57
70
67
23
3
23.7
15.4
40.5
50.5
4.6
5a
9.2
27
by standard coupling conditions with
9 gave the amide 4f
(Scheme 2). In contrast, the reaction sequence for the pyridines
attached at the 2-position (Table 3, 5a–c) was reversed. For
example, 9 was coupled directly with the amine obtained from
Raney-Ni reduction of the nitrile 15, which then underwent reaction
with 6-(bromomethyl)-picolinonitrile to afford compound 3b.
To further probe the effect of making the compounds more
hydrophilic replacements of the methoxy group were evaluated
(Table 3). Incorporation of a methoxyethoxy ether with the potent
amide moieties identified from Table 2 afforded compounds 5a–c.
The antiviral potency ranged from an IC50 of 2.0 nM for the chloride
analog 5a to 32.3 nM for the cyano analog 5b. As anticipated these
compounds had an improved fold AGP fusion shift in the range of
1.5–3 and an acceptable plasma human protein binding. The po-
tent antiviral activity (IC50 of 3.3 nM) of the acetamide 5e was
2h
2p
4d
4f
4g
4i
4l
5a
3b
Dog
11.2
0.75
0.15
0.58
1.57
0.41
0.92
0.01
0.52
14.5
5.11
0.20
1.33
2.73
0.65
0.48
0.02
0.72
5.0
0.4
6.0
10.3
34.7
26.7
8.3
5.2
4.9
3.0
1.5
5.4
3.3
13.5
13.2
3.0
2.8
1.3
0.8
35
36
4
21
37
10
5
15.0
36.5
30.0
23.3
32.04
21.1
156.6
42.7
<1
15
a
Clearance (CL), volume of distribution (Vdss) and half life (T1/2) calculated fol-
lowing a 10 mol/kg iv dose in rat and 5 mol/kg iv dose in dog. Oral bioavailability
l
l
encouraging since the c logP was 2.6 reflected in the low fold
AGP fusion shift of 1.2. Other replacements such as the sulfoxide

6954
R. Skerlj et al. / Bioorg. Med. Chem. Lett. 21 (2011) 6950–6954
compounds is similar to that of compounds 4 (Scheme 2). Although,
CO2H
CO2H
Br
CO2Et
Br
a,c,d
e, f
a-c
as exemplified by 3b the nitrile of 15 was first reduced to the pri-
mary amine which allowed installation of the amide followed by
introduction of the left hand side pyridine nitrile group.
Compound 4f was selected for further evaluation. The selectiv-
ity of 4f and related analogs was evaluated in Ca2+ flux assays
against a series of other closely related G-protein-coupled recep-
tors (GPCRs), which included CCR1, CCR2b, CCR4, CXCR1, CXCR2
and CXCR4, and were found to be non-inhibitory. In addition 4f
and analogs were not cross reactive to the M2 muscarinic receptor.
When tested against a panel of 5 isoforms of CYP 450 4f was found
Cl
N
9
NC
N
8
N
CO2H
g
F
N
H2N
N
F
N
11
10
O
h-k
l
CN
OH
N
H2N
BocHN
MeO
CN
14
13
12
to be non-inhibitory at concentrations >10 lM. Although 4f pro-
gressed to a 7-day safety study in rat and had an acceptable NOAEL
in parallel it was found to have an unacceptable cardiovascular
safety profile based on hERG inhibition, IC50 of 0.25 lM.
In conclusion a series of CCR5 antagonists were successfully
optimized to improve potency and achieve an acceptable in vitro
and in vivo profile but the series was not further progressed due
to cardiovascular safety concerns. In due course we will report
our efforts in mitigating the hERG liabilities.
m
N
H
N
n, o
N
N
N
NH2
MeO
CN
15
q, p, r
16
p
3b
4f
Scheme 2. Reagents and conditions: (a) m-CPBA, CH2Cl2; (b) POCl3, reflux, 44% for
two steps; (c) NaOH, EtOH, 90 °C, 88%; (d) TMSCN/Me2NCOCl, DMF, 80 °C, 82%; (e)
NaNO2, HBF4, 0 °C; (f) heptane, 90 °C, 36% for two steps; (g) t-BuLi, Et2O, À78 °C,
then CO2, À78 °C to rt, 73%; (h) MsCl, CH2Cl2, 76%; (i) NaCN, DMSO, 45 °C, 63%; (j)
CH3SO3H, CH3CN/EtOAc, 70 °C, 1 h; (k) NH4OH, 90% for two steps; (l) 1-ethylmeth-
yl-4-piperidone iodide, EtOH/H2O, 100 °C, 87%, >99% ee; (m) 4-methoxyaniline,
NaBH(OAc)3, CH2Cl2, 98%; (n) 4-methylnicotinoyl chloride, THF, Et3N, 87%; (o)
BH3ÁTHF, 65 °C, 90%; (p) HOBt, EDCI, DIPEA, 9, DMF, 63%; (q) Raney Ni, H2, MeOH,
62%; (r) 6-(bromomethyl)-picolinonitrile, DIPEA, KI, CH3CN, 80 °C, 42%.
References and notes
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Brown, S.; Jackson, J. B.; Coombs, R. W.; Glesby, M. J.; Flexner, C. W.; Bridger, G.
J.; Badel, K.; MacFarland, R. T.; Henson, G. W.; Calandra, G. J. Acquired Immune
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5d, hydrogen 5f and morpholine 5g had a negative impact on the
antiviral activity. However, although the data for compounds 5a–
c was promising the PK data in rat and dog was poor. For instance,
the oral bioavailability of a representative compound, 5a in dog
was <1% (Table 4).
5. Moyle, G.; DeJesus, E.; Boffito, M.; Wong, R. S.; Gibney, C.; Badel, K.;
MacFarland, R.; Calandra, G.; Bridger, G.; Becker, S. Clin. Infect. Dis. 2009, 48,
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A series of compounds was also synthesized in which the pyri-
dine ring was attached at the 2-position (Table 3) based on the
SAR established earlier with the aniline series (Table 1). The analogs
containing a nitrile group at the 3-position of the phenyl ring
(2n–p) were found to have potent anti-HIV-1 activity (IC50 of
1.0–14.0 nM) but required an improvement in ADME properties.
By utilizing the functionalized pyridine amides discussed above
and introducing a pyridine ring to the 2o analog compounds 3a–c
were synthesized. These compounds met the desired in vitro prop-
erties which included potency (IC50 of 3.5–3.9 nM), fold AGP fusion
shift (2.4–4.4) and human plasma protein binding (79–91%). We
were disappointed, however, to find that these compounds had
marginal pharmacokinetic properties. For example, the oral bio-
availability of 3b in dog was 15% (Table 4). The preparation of these
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