Modulators of the human CCR5 receptor. Part 3: SAR of substituted 1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]-piperidinyl phenylacetamides

Article abstract of DOI:10.1016/j.bmcl.2006.03.089

SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl] propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human CCR5 chemokine receptor

Full text of DOI:10.1016/j.bmcl.2006.03.089

Bioorganic & Medicinal Chemistry Letters 16 (2006) 3533–3536
Modulators of the human CCR5 receptor. Part 3: SAR of
substituted 1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]-
piperidinyl phenylacetamides
John G. Cumming,a,* Simon J. Brown,a Anne E. Cooper,b Alan W. Faull,a
Anthony P. Flynn,a Ken Grime,b John Oldfield,a John S. Shaw,a Emma Shepherd,a
Howard Tuckera and David Whittakera
aRespiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
bAstraZeneca R&D Charnwood, Bakewell Road, Loughborough LE11 5RH, UK
Received 20 February 2006; revised 24 March 2006; accepted 25 March 2006
Available online 2 May 2006
Abstract—SAR and PK studies led to the identification of N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[4-methanesulfonylphenyl]
propyl}piperidin-4-yl)-N-ethyl-2-[4-methanesulfonylphenyl]acetamide as a highly potent and selective ligand for the human
CCR5 chemokine receptor with good oral pharmacokinetic properties.
Ó 2006 Elsevier Ltd. All rights reserved.
The chemokine receptor CCR5 is expressed on T-lym-
phocytes, monocytes, macrophages, dendritic cells,
microglia and other cell types. These receptors detect
and respond to several chemokines, principally ‘regulat-
ed on activation normal T-cell expressed and secreted’
(RANTES) and macrophage inflammatory proteins
(MIP) MIP-1a and MIP-1b, resulting in the recruitment
of cells of the immune system to sites of disease. CCR5
is also a co-receptor for HIV-1 and other viruses, allow-
ing these viruses to enter cells. Individuals who are
homozygous for a 32-base pair deletion in the gene
encoding CCR5, whilst otherwise healthy, are strongly
protected against HIV-1 infection.1 Other studies indi-
cate a role for CCR5 and its ligands in disorders such
as rheumatoid arthritis,2 multiple sclerosis,3 transplant
rejection4 and inflammatory bowel disease.5 These
observations suggest that molecules that modulate the
CCR5 receptor would have potential benefit in a wide
range of diseases. The antagonism of CCR5 by small
molecules has become an active area of research in many
pharmaceutical companies.1,6
We have previously reported our initial investigations
into small molecule inhibitors of CCR5 which led to
the identification of 1-(3,3-diphenylpropyl)-piperidinyl
amides 1 as a suitable lead compound for further opti-
misation.7 Further optimisation led to the identification
of compound 2a as a potent (IC50 1.7 nM) and bioavail-
able CCR5 antagonist.8 We now wish to report further
optimisation of pharmacokinetics (PK) and potency in
this series.9
In order to study the PK of 2a in more depth, and to
determine the absolute configuration that afforded
greater potency, we developed an enantioselective
synthesis of 2a that could also be used to prepare
analogues with different substitution on the undecorated
phenyl ring. The route (Scheme 1) involved the
diastereoselective conjugate addition of an aryl-cuprate
species under the control of an imidazolidinone chiral
auxiliary (4).10 The substrate for the conjugate addition
(5) was prepared by reaction of the acid chloride derived
from cinnamic acid 3 with the imidazolidinone 4.
Addition of a cuprate prepared from an aryl Grignard
to 5 mediated by di-n-butylboron triflate proceeded
smoothly to give the product 6 as a single diastereoiso-
mer (>95% dr by 1H NMR). The auxiliary was removed
either by reduction to the alcohol with subsequent
Keywords: CCR5 modulator; CCR5 antagonist; Chemokine receptor;
CCR5.
oxidation to the aldehyde 7 using Dess–Martin
periodinane, or by reduction directly to the aldehyde 7
*
Corresponding author. Tel.: +44 01625517755; fax: +44
01625510823; e-mail: john.cumming@astrazeneca.com
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.03.089

3534
J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3533–3536
Et
N
R1
N
N
O
N
O
SO2Me
SO2Me
2a: R1 = SO2Me; R2 = H
2b: R1 = R2 = F
1
R2
O
R
Me
N
HN
Ph
O
O
O
O
O
4
b
Me
Me
Me
N
N
N
N
OH
a
MeO2S
MeO2S
MeO2S
MeO2S
Me
Ph
Me
Ph
3
5
6
c, d
or e
Et
N
Et
MeO2S
N
HN
O
O
SO2Me
N
O
8
SO2Me
f
R
R
9
7
i
n
Scheme 1. Reagents and conditions: (a) SOCl2, CH2Cl2, rt; 4, Pr2NEt, rt; (b) ArMgBr, CuI, TMEDA, THF, À78 °C; Bu2BOTf, 5, À78 °C to rt;
(c) LiAlH4, THF, 0 °C; (d) DMP, CH2Cl2, rt; (e) DIBAL-H, CH2Cl2, À78 °C; (f) 8, NaBH(OAc)3, CH2Cl2, rt.
with
di-iso-butylaluminium
hydride.
Reductive
high clearance and was 13% bioavailable. The PK
parameters of the lead compound 1 were similar to those
of 9a. In contrast, the di-4-fluorophenyl analogue 2b had
a low clearance, a longer half-life and was 56% bioavail-
able. It appears that the fluoro groups are acting to
block oxidative metabolism at the 4-position of the
phenyl rings, however this substitution pattern is also
associated with loss of potency (IC50 780 nM).
We decided to try to reduce metabolism of 9a without
a loss of potency by exploring substitution of the
undecorated phenyl. The results (Table 1) demonstrate
clear SAR around this phenyl ring. The 3-chloro (9d)
analogue maintained the potency of 9a and the 3-fluoro
(9b) analogue gave an increase in potency. Other small
3-substituents such as trifluoromethyl (9h), cyano (9p)
and methoxy (9q) were somewhat less potent. More
bulky groups such as isopropyl (9o) and tert-butyl (9n)
led to a bigger drop in potency. The 4-fluoro analogue
(9c) was around 50-fold less potent than 9a, while other
4-substituents such as methoxy (9f) gave a large drop in
potency. The 3,4-di-fluoro (9e) and 3,4,5-tri-fluoro (9i)
amination of 7 with 4-substituted piperidine 88 gave
the target compounds 9. The 3-trifluoromethyl analogue
9h was accessed11 by the conjugate addition of 4-thio-
anisolemagnesium bromide (10) to the 3-trifluorometh-
ylcinnamoyl derivative (11) of the opposite enantiomer
of the auxiliary, with subsequent S-oxidation to the
methanesulfonyl intermediate 6h (Scheme 2).
CCR5 binding potency was assayed by displacement of
the binding of [125I]MIP-1a to membranes prepared
from Chinese hamster ovary (CHO) cells stably express-
ing recombinant human CCR5.12 The results are shown
in Table 1. Compound 9a was approximately twice as
potent as its racemate, 2a, suggesting that it was the
more active enantiomer. The rat PK of compound 9a,
the lead compound 1 and the di-4-fluorophenyl ana-
logue 2b was studied. Data for clearance (Cl), volume
of distribution (Vss) and terminal half-life (t1/2) deter-
mined from iv dosing, and oral bioavailability (F%)
are shown in Table 2. Compound 9a had a moderately
O
F3C
MeS
Me
N
HN
Ph
O
O
O
ent-4
O
O
MgBr
F3C
Me
10
Me
F3C
Me
N
N
N
N
OH
a
b, c
MeO2S
Me
Ph
Me
Ph
11
6h
Scheme 2. Reagents and conditions: (a) SOCl2, CH2Cl2, rt; ent-4, iPr2NEt, rt; (b) 10, CuI, TMEDA, THF, À78 °C; nBu2BOTf, 11, À78 °C to rt; (c)
m-CPBA, CH2Cl2, rt.

J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3533–3536
3535
Table 1. CCR5 binding data for diphenylpropylpiperidine compounds
and good rat PK, compound 9g was selected for further
studies. The (S)-enantiomer of 9g was prepared via the
same synthetic route (Scheme 1) but using the opposite
enantiomer of the chiral auxiliary. The chiral purities
of 9g and ent-9g were determined by analytical chiral
HPLC to be >97% ee and 96% ee, respectively. The
CCR5 binding IC50 of ent-9g (which contained 2% of
the (R)-isomer) was 40 nM, showing that essentially all
the potency resides in the (R)-isomer. The absolute con-
figuration of 9g was confirmed as (R) by single crystal
X-ray of the product from the conjugate addition reac-
tion, 6g (Fig. 1). Compound 9g was tested for its ability
to inhibit MIP-1b-stimulated calcium transients in
human AlloT cells and was found to have an IC50
of 0.12 nM. Also 9g was shown to have an IC50 of
2.8 nM in an assay measuring the inhibition of chemo-
taxis of human AlloT cells in response to MIP-1b. 9g
was found to be extremely selective for binding to
CCR5 over other chemokine receptors (human CCR1,
CCR2b, CCR3, CXCR1 and CXCR2) and other
GPCRs (human M1, M2 and 5-HT2A): it showed less
than 50% inhibition at 10 lM in all cases, implying that
its selectivity for CCR5 versus these other receptors is of
the order of 30,000-fold or better. Compound 9g had
acceptable physicochemical properties: logD7.4 = 2.2,
plasma protein binding = 72% and 82% in rat and hu-
man plasma, respectively, thermodynamic aqueous solu-
bility at pH 7.4 = 160 lM, pKa = 7.5. Compound 9g
showed excellent oral bioavailability in the dog (Table
3). The iv and po PK profiles for 9g in the rat and
dog are shown in Figures 2 and 3, respectively.
Et
N
MeO2S
N
O
SO2Me
R
9
a
IC50 (nM)
Compound
R
2a
2b
9a
9b
9c
9d
9e
9f
—
—
1.7
780
0.76
0.22
46
H
3-F
4-F
3-Cl
1.0
21
3,4-Di-F
4-OMe
3,5-Di-F
3-CF3
132
0.32
20
9g
9h
9i
3,4,5-Tri-F
2,3-Di-F
2,6-Di-F
2,5-Di-F
3-F-5-Cl
3-tBu
25
20
9j
9k
9l
560
32
9m
9n
9o
9p
9q
1.1
500
110
56
3-iPr
3-CN
3-OMe
25
a IC50s were derived from triplicate measurements whose standard
errors were normally <5% in a given assay. Assay-to-assay variability
was within 2-fold based on the results of the standard compound 1.
Compound 9g showed good stability to metabolism in
human hepatocytes in vitro (Clint = 3 lL/min/106 cells)8
Table 2. Rat in vivo PK parameters for selected compounds
a
Vss (L/kg)
a
t1/2 (h)
Compound
Cla (mL/min/kg)
F%b
1
54
10
43
54
28
20
2.7
1.7
5.1
5.3
5.3
7.1
0.9
2.4
0.8
1.8
2.6
5.2
11
56
13
nt
2b
9a
9b
9g
9m
38
32
nt, not tested.
a Compounds dosed 1–2 mg/kg iv, n = 3 animals.
b Compounds dosed 5–10 mg/kg po, n = 3 animals.
analogues were intermediate in potency between the
3- and 4-fluoro compounds. ortho-Substitution with
fluoro (9j and 9l) led to a similar reduction in potency,
while the analogue with a fluorine in both ortho
positions (9k) was substantially less potent. However,
the 3,5-di-fluoro analogue (9g) showed a significant in-
crease in potency (IC50 0.32 nM). The 3-fluoro-5-chloro
analogue (9m) had similar potency to 9a.
Figure 1. Single crystal X-ray structure of 6g (R = 3,5-di-F) showing R
absolute configuration at induced chiral centre.
The rat PK of compounds 9b, 9g and 9m was studied. 9b
had a high clearance and short half-life suggesting that
the 3-fluoro was not having an effect on the metabolism.
However, the 3,5-di-halo compounds (9g and 9m) had a
lower clearance, longer half-lives and good bioavailabil-
ity. It appears that the incorporation of a halogen into
both meta positions reduces oxidative metabolism of
the phenyl ring. On the basis of its excellent potency
Table 3. Dog in vivo PK parameters for compound 9g
Cl (mL/min/kg)a
F%b
a
Vss (L/kg)
a
t1/2 (h)
18
5.7
3.9
86
a Compound dosed 1 mg/kg iv, n = 3 animals.
b Compound dosed 4 mg/kg po, n = 2 animals.

3536
J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 16 (2006) 3533–3536
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0
2
4
6
8
Time (h)
Figure 2. PK profile for compound 9g in rat; dosing at 2 mg/kg iv
(n = 3) and at 4 mg/kg po (n = 3).
1.00
6. (a) Kazmierski, W. M.; Peckham, J. P.; Duan, M.; Kenakin,
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i.v.
0.10
p.o.
0.01
0
5
10
15
20
25
30
Time (h)
Figure 3. PK profile for compound 9g in dog; dosing at 1 mg/kg iv
(n = 3) and at 4 mg/kg po (n = 2).
and was tested for inhibition of human cytochrome P450
activity, achieving our target of IC50 >10 lM versus the
1A1, 2C19, 2C9 and 3A4 isoforms. However, 9g gave an
IC50 of 1.6 lM versus the 2D6 isoform and was found to
have an IC50 of 7.3 lM in a hERG ion channel binding
assay.13 In view of the excellent potency and PK proper-
ties of 9g, we predicted that an acceptable margin with
respect to these two off-target activities could be
achieved in humans.
In summary, SAR and PK studies in the homochiral
1-[3-(4-methanesulfonylphenyl)-3-phenylpropyl]piperidine
series have led to the identification of 9g as a highly
potent antagonist at the human CCR5 receptor with
good oral PK properties. This compound has potential
as an oral treatment of diseases in which CCR5 plays
a role.
7. Burrows, J. N.; Cumming, J. G.; Fillery, S. M.; Hamlin,
G. A.; Hudson, J. A.; Jackson, R. J.; McLaughlin, S.;
Shaw, J. S. Bioorg. Med. Chem. Lett. 2005, 15, 25.
8. Cumming, J. G.; Cooper, A. E.; Grime, K.; Logan, C. J.;
McLaughlin, S.;Oldfield, J.;Shaw, J. S.;Tucker, H.;Winter,
J.; Whittaker, D. Bioorg. Med. Chem. Lett. 2005, 15, 5012.
9. (a) Burrows, J.; Cooper, A.; Cumming, J.; McInally, T.;
Tucker, H. WO 01/087839, 2001; Chem. Abstr. 2002, 135,
371644; (b) Cumming, J.; Tucker, H. WO 03/042177, 2003;
Chem. Abstr. 2003, 138, 385312.
Acknowledgments
The authors thank our colleagues Lucy C. Ashman, Tu-
seef Chaudhary, Susan Mellor and Lorraine D. Newbo-
ult for developing and carrying out the biological assays,
Anthony Atkinson, Jane Kenny and Steve Trigg for car-
rying out the PK studies and Anne Ertan for determin-
ing the X-ray crystal structure.
10. van Heerden, P. S.; Bezuidenhoudt, B. C. B.; Ferreira, D.
Tetrahedron 1997, 53, 6045.
11. An explosion hazard in the preparation of 3-trifluorometh-
ylphenylmagnesium bromide has been reported, see: Urben,
P. G. Ed.; Bretherick’s Handbook of Reactive Chemical
Hazards; 5th ed.; Butterworth: Heinemann, 1995; p 852.
12. For experimental procedure, see Ref. 8.
References and notes
1. For a review of CCR5 as a target for HIV-1 and small
molecule CCR5 ligands, see: Kazmierski, W.; Bifulco, N.;
13. Springthorpe, B.; Strandlund, G. WO 2005037052; Chem.
Abstr. 2005, 142, 426388.