Balancing hERG affinity and absorption in the discovery of AZD5672, an orally active CCR5 antagonist for the treatment of rheumatoid arthritis

Article abstract of DOI:10.1016/j.bmcl.2011.12.117

Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenylacetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion channel. Replacement of one aromatic ring in the diphe

Full text of DOI:10.1016/j.bmcl.2011.12.117

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1655–1659
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Balancing hERG affinity and absorption in the discovery of AZD5672,
an orally active CCR5 antagonist for the treatment of rheumatoid arthritis
⇑
John G. Cumming , Howard Tucker, John Oldfield, Colin Fielding, Adrian Highton, Alan Faull,
Martin Wild, Dearg Brown, Stuart Wells, John Shaw
Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Modifications to a series of potent and selective substituted 1-(3,3-diphenylpropyl)-piperidine phenyl-
acetamide CCR5 antagonists were explored with the aim of reducing affinity at the hERG cardiac ion
channel. Replacement of one aromatic ring in the diphenylpropyl region with less lipophilic, saturated
heterocyclic rings and subsequent optimisation of the other phenyl ring led to the identification of clin-
ical compound AZD5672 which retained excellent potency while reducing hERG affinity. Modulating
lipophilicity affected the interplay between potency, hERG affinity and absorption. AZD5672 was found
to have an acceptable balance of these properties and was progressed to a phase II clinical trial to test
the hypothesis that inhibition of CCR5 will bring benefits in the treatment of rheumatoid arthritis.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 19 October 2011
Revised 23 December 2011
Accepted 24 December 2011
Available online 2 January 2012
Keywords:
CCR5 antagonist
Chemokine receptor
hERG
Rheumatoid arthritis (RA) is a chronic inflammatory disease
characterised by a massive infiltration of leucocytes into the syno-
vial tissue and synovial fluid, mediated by a variety of adhesion
molecules and chemokines. Synovial tissue from patients with RA
shows abundant expression of various chemokines and chemokine
receptors, including CCR5 and its ligands.1,2 Furthermore, CCR5
expression has been shown to be significantly increased on RA
synovial fluid monocytes/synovial tissue, compared with normal
and RA peripheral blood monocytes.1,2 These results suggest that
small molecule antagonists at the CCR5 receptor may have benefit
in treating RA. Further supporting evidence for this hypothesis
came when significant effects on clinical arthritis score were seen
with the small molecule CCR5 antagonist SCH-X in a rhesus mon-
key collagen-induced arthritis model.3 CCR5 is also a co-receptor
for HIV-1 and other viruses, allowing 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.4 The antagonism of CCR5 by
small molecules has become an active area of research in many
pharmaceutical companies5 culminating in the approval of marav-
iroc for use in combination antiretroviral treatment of patients in-
fected with CCR5-tropic HIV-1 virus.6
IC50 = 0.32 nM) and selectivity together with good oral PK profiles
in rat and dog. However, compound 1 showed moderate activity
against the hERG ion channel (binding IC50 = 7.3 lM) which is an
indicator of a cardiotoxicity risk. The cardiac safety profile of 1
was investigated pre-clinically in conscious, telemetered dogs
and a sustained prolongation of the QTc interval was observed at
a dose of 50 mg/kg po with no effects at 5 mg/kg. The margin be-
tween the no effect free plasma concentration and the predicted
free Cmax at an efficacious dose in humans (7.5 nM) was less than
10-fold which was judged to be insufficient, precluding further
development of compound 1.
O
NH
H
N
N
F
N
N
F
H
maraviroc
Previous work from this laboratory described the discovery and
optimisation of substituted 1-(3,3-diphenylpropyl)-piperidine
MeO2S
N
phenylacetamides7 leading to compound 1,
a potent CCR5
antagonist.7c This compound had excellent CCR5 potency (binding
N
O
SO2Me
⇑
Corresponding author.
E-mail address: john.cumming@astrazeneca.com (J.G. Cumming).
1
F
F
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.117

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J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1655–1659
Inhibition of the hERG channel is a common challenge for
CCR5 binding potency was assayed by displacement of the bind-
medicinal chemists developing drugs acting at CCR55c,5d,6c,8 and
at chemokine receptors generally9 due to pharmacophoric features
shared with hERG blockers, in particular a basic amine which inter-
acts with the TM7 glutamate residue in chemokine receptors.10
Compound 1 is one of a group of CCR5 antagonists that have as a
common feature a central piperidine or tropane ring substituted
on the N-atom with a 3-phenylpropyl group which carries a variety
of substituents in the 3-position. Examples include maraviroc
(where the 3-substituent is a (4,4-difluorocyclohexyl)carbonylami-
no group),6b a series of 1-sulphonamido-2-aryl-4-(piperidin-1-yl)-
butanes11 and 1,3,4-trisubstituted pyrrolidines.12 There is a strict
requirement for the 3-phenyl substituent11 but the variety of the
other 3-substituents (amides, sulphonamidomethyl and aryl) indi-
cates that this site of interaction with the receptor is tolerant of
size and polarity. We also hypothesised that removing an aryl ring
and reducing lipophilicity by introducing heteroatoms might
reduce the affinity with the hERG channel.8 We therefore investi-
gated the replacement of the ‘upper’ phenyl ring in the diphenyl-
propyl series with piperazine and piperidine.13 The project goal
was to identify a potent and selective CCR5 antagonist with good
ing of [125I]MIP-1
a to membranes prepared from Chinese hamster
ovary (CHO) cells stably expressing recombinant human CCR5.14
Selected compounds were also tested for in vitro metabolic stabil-
ity in human liver microsomes and binding to the hERG ion chan-
nel.15 The results are presented in Table 1.
Replacement of the ‘upper’ phenyl in 1 with a piperazine (3),
N-linked piperidine (4) or C-linked piperidine (5) gave compounds
with moderate to good activity depending on the substituent R in
the 4-position on the ring. Comparison between the three rings
keeping the substituent R constant reveals that C-linked piperidine
is more potent than N-linked piperidine and piperazine (compare
R = methyl: 3a, 4a, 5a; R = acetyl: 3d, 4c, 5c; R = ethylsulfonyl: 3f,
5e). Analogues where R is a sulfonyl group showed particularly
good potency with the N-trifluoromethylsulfonyl C-linked piperi-
dine (R)-5f having an IC50 below 0.1 nM. Compounds containing
the methylsulfonyl substituent (3e and 5d) showed significantly
reduced hERG activity (IC50 = 25 nM). The less lipophilic piperazine
analogue 3e showed good metabolic stability but lower CCR5 po-
tency, while the more lipophilic C-linked piperidine analogue
(R)-5d had good CCR5 potency but inferior metabolic stability.
Previous SAR studies in the diphenylpropyl series (exemplified
by 1) had shown that substituting the ‘lower’ phenyl with halogen
in the meta position led to maintained or improved potency with
an improvement in metabolic stability.7c We next investigated
whether the same SAR would carry over into the piperazine and
C-linked piperidine series, aiming to identify a compound with
the desired potency and DMPK properties. The results are shown
in Table 2.
oral PK properties and hERG channel binding IC50 >30 lM. Earlier
we had found that hERG activity in the series could be reduced
by incorporation of electron withdrawing groups close to the
central nitrogen, lowering its basicity, but this change was
accompanied by a large reduction in CCR5 potency (results not
shown).
Racemic piperazine and N-linked piperidine analogues 3 and 4
were prepared starting from intermediate 27c according to the
route shown in Scheme 1. Single enantiomers in the piperazine
series were prepared starting from (3S)-3-hydroxy-3-phenylpro-
pane-1-tosylate (Scheme 2). The reaction of the carbinol with
methanesulfonyl chloride proceeds with inversion of configuration
due to attack of chloride ion on the initially formed mesylate. A
second inversion of configuration occurs during reaction with the
appropriately substituted piperazine giving compounds (S)-3. The
synthesis of the racemic C-linked piperidines 5 is shown in Scheme
3. This route allowed rapid exploration of the piperidine substitu-
ent as this was elaborated in the final step by acylation, sulfonyla-
tion or reductive alkylation. The single enantiomers (R)-5 and 7
were prepared using a route similar to that previously reported7c
for the synthesis of compound 1 involving dibutylboron triflate
Adding substituents to the 3- and 5-positions of the ‘lower’ phe-
nyl ring did indeed generally retain or improve potency, with the
exception of polar methylsulfonyl (7a) and methoxy (7b). Methyl
substituents (7d and 7g) led to a decrease in metabolic stability,
possibly by introducing additional sites for oxidation. Introducing
too much lipophilicity (7g-7j) caused the hERG binding IC50 to drop
back below 10 l
M. Matched molecular pair analysis17 examining
the effect on CCR5 and hERG potency in changing the ‘upper’ ring
from phenyl (as in 1) to C-linked piperidine (as in (R)-5d and 7)
showed firstly that the SAR was parallel in terms of substitution
on the ‘lower’ aryl ring, and secondly that the piperidine ring gave
a mean increase in CCR5 pIC50 of 0.34 log units (s.e. = 0.09, N = 8)
together with a mean reduction in hERG pIC50 of 0.92 log units
(s.e. = 0.10, N = 7). This structural change is accompanied by a drop
in lipophilicity (ꢀ1 unit in measured logD7.4) as well as saturation
promoted conjugate addition of an arylcuprate to an
a
,b-unsatu-
rated acyl imidazolidinone chiral auxiliary (Scheme 4).
N
N
O
N
R
X
HN
O
a, b, c
d
N
N
O
Cl
N
SO2Me
SO2Me
SO2Me
2
3: X = N
4: X = CH
Scheme 1. Reagents and conditions: (a) PhCOCH2CH2Cl, K2CO3, DMF, rt. (b) NaBH4, EtOH, 0 °C. (c) MeSO2Cl, CH2Cl2, Et3N, 0 °C. (d) Substituted piperazine/piperidine, Et3N,
CH2Cl2, rt.
N
N
R
OH
N
a, b
c
N
O
N
O
Cl
N
OTs
SO2Me
SO2Me
(S)-3
Scheme 2. Reagents and conditions: (a) 2, K2CO3, DMF, 80–90 °C. (b) MeSO2Cl, CH2Cl2, Et3N, 0 °C. (c) Substituted piperazine, Et3N, CH2Cl2, rt.

J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1655–1659
1657
O
O
O
O
N
O
N
O
N
a
b
O
O
O
O
O
c, d
O
N
R
N
O
N
e, f, g
O
O
N
H
S
O
O
5
Scheme 3. Reagents and conditions: (a) (EtO)2P(O)CH2COOEt, LHDMS, THF, 0 °C. (b) H2, 20% Pd/C, EtOH. (c) LiAlH4, Et2O, –10 °C. (d) Dess–Martin periodinane, CH2Cl2, rt. (e) 2,
NaBH(OAc)3, CH2Cl2, rt. (f) TFA, rt. (g) R0COCl or R0SO2Cl or R’CHO with NaBH(OAc)3.
O
Me
O
N
HN
Ph
Me
N
O
O
MeO2S
b
O
8
OH
N
Me
Me
Me
N
N
N
N
MeO2S
N
O
MeO2S
Me
Ph
a
R'
c, d
MeO2S
N
MeO2S
N
N
O
N
H
SO2Me
e
O
R'
R'
7
i
Scheme 4. Reagents and conditions: (a) SOCl2, CH2Cl2, rt; 8, Pr2NEt, rt. (b) ArMgBr, CuI, TMEDA, THF, –78 °C; nBu2BOTf, –78 °C to rt. (c) LiAlH4, THF, 0 °C. (d) Dess–Martin
periodinane, CH2Cl2, rt. (e) 2, NaBH(OAc)3, CH2Cl2, rt.
of one aromatic ring so the concomitant reduction in hERG binding
is in line with precedent from other hERG SAR studies.8,18
However, we were aware that for such high molecular weight
compounds (e.g. 6 has MWt = 641) reducing lipophilicity was
highly likely to reduce oral absorption due to efflux by transport-
ers.19 Compounds 6 and 7e had the best in vitro profiles so their
in vivo pharmacokinetic parameters in rat and dog were measured
(Table 3).
While 6 showed only moderate bioavailability in dog and very
high plasma clearance in rat, 7e showed good oral bioavailability
in both species. After further profiling 7e was selected as a candi-
date drug and became AZD5672. Additional data for 7e is shown in
Table 4.
primates, and intrinsic clearance data in human hepatocytes) tar-
geting a minimum plasma concentration at steady state of 3-fold
the whole blood internalization A2, calculation of the margin be-
tween hERG IC50 in an electrophysiology assay and the predicted
free maximum plasma concentration, and comparing this with
the corresponding values and dog telemetry results for compound
1 (Table 5). Compound 7e showed a 25-fold improvement in the
margin between hERG and predicted free Cmax compared to com-
pound 1, arising from a combination of greater potency, lower free
fraction and reduced hERG activity, while the predicted PK was
similar for the two compounds.
In summary, replacement of one phenyl ring in diphenylpropyl
1 with a C-linked piperidine led to the discovery of AZD5672, a po-
tent and selective antagonist of CCR5 with reduced cardiac safety
liability and excellent PK properties suitable for clinical testing of
the hypothesis that inhibition of CCR5 will lead to beneficial ef-
fects on rheumatoid arthritis. This structural change retained
sub-nanomolar potency at CCR5 while reducing lipophilicity: li-
gand lipophilicity efficiency (LLE = pIC50–logD7.4) was improved
by almost 1 unit (7.3 for 1 vs 8.1 for AZD5672), consistent with
an improved margin against hERG.9 Absorption of AZD5672 was
found to be limited by efflux by Pgp transporter, consistent with
its physicochemical properties (a large, basic molecule with
logD7.4 of 1.5)19 but pre-clinical PK data and human PK modeling
provided confidence to progress the compound into clinical
trials.20
The sub-nanomolar affinity of 7e at the CCR5 receptor trans-
lated into highly potent inhibition of MIP-1b-induced chemotaxis
in allo T cells and CCR5 receptor internalization in human whole
blood. 7e showed good aqueous solubility and weak or no inhibi-
tion of the 5 major cytochrome P450 (CYP) isoforms, this being an-
other improvement over compound 1 which had an IC50 of 1.6 lM
versus CYP2D6.7c,6d Permeability as measured by the Caco2 assay
was moderate with an efflux component, which reduced at a
higher concentration of 7e indicating there was potential for satu-
ration of efflux transporters.
The likely safety margin with respect to QT prolongation in hu-
mans was modelled based on a prediction of human PK (extrapo-
lating from PK parameters measured in mouse, rat, dog, and

1658
J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1655–1659
Table 1
CCR5 binding, human microsomal intrinsic clearance, hERG binding and logD7.4 data for selected compounds
N
R
X
Y
N
O
SO2Me
3: X = N, Y = N
4: X = CH, Y = N
5: X = N, Y = CH
Compds
R
CCR5 IC50 (nM)a
HLMb
hERG IC50
(
l
M)c
logDd
1
3a
3b
3c
3d
3e
3f
(S)-3g
(S)-3h
4a
4b
4c
5a
5b
5c
(R)-5d
5e
—
0.32
363
5.0
3.1
229
39
8
—
7.3
—
13
3.2
—
25
—
3.2
5.8
—
—
—
—
—
—
25
—
1.2
—
2.2
0.9
2.7
3.2
0.9
0.8
1.0
2.9
1.8
2.0
3.7
0.9
1.0
2.4
1.4
1.1
1.6
3.4
2.2
Methyl
Phenyl
3-Fluorophenyl
Acetyl
Methylsulfonyl
Ethylsulfonyl
Trifluoromethylsulfonyl
2,2,2-Trifluoroethylsulfonyl
Methyl
Benzyl
Acetyl
Methyl
Benzyl
26
22
—
<3
52
33
47
—
—
21
—
>150
—
31
61
28
28
15
1.6
8.9
339
162
83
126
8.9
37
1.1
2.4
<0.1
5.4
Acetyl
Methylsulfonyl
Ethylsulfonyl
Trifluoromethylsulfonyl
2,2,2-Trifluoroethylsulfonyl
(R)-5f
5g
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 a standard compound.
b
Clint values (lL/min/mg microsomal protein). For procedure see Ref. 16; — = not tested.
For procedure see Ref. 15; — = not tested.
LogD7.4 measured or predicted with AZlogD (see Ref. 18).
c
d
Table 2
CCR5 binding, human microsomal intrinsic clearance, hERG binding and logD7.4 data for selected compounds
N
MeO2S
N
X
N
O
SO2Me
R'
6: X = N
7: X = CH
Compds
R0
CCR5 IC50 (nM)a
HLMb
hERG IC50
(l
M)c
logDd
6
3,5-Difluoro
3-Methylsulfonyl
3-Methoxy
3-Fluoro
3-Methyl
3,5-Difluoro
3-Fluoro-5-chloro
3,5-Dimethyl
3-Chloro
3-Trifluoromethyl
3,5-Dichloro
3.7
794
5.0
0.68
0.44
0.26
0.69
<0.1
0.55
3.5
8
—
>32
—
32
35
-
24
14
4.0
7.9
7.9
6.5
1.2
0.6
1.2
1.4
1.5
1.5
1.6
1.9
1.8
1.9
2.6
7a
7b
7c
7d
7e
7f
7g
7h
7i
45
18
104
18
22
>150
32
17
18
7j
<0.1
a,b,c,d
see footnotes to Table 1.
In a phase IIb study in RA patients AZD5672 had robust, once
daily oral PK properties with the target Cmin of 2 nM being achieved
with a dose of 50 mg once daily. Unfortunately there was no statis-
tically significant effect of AZD5672 on signs and symptoms of RA,
even at a 150 mg dose. High levels of receptor occupancy and max-
imal inhibition of CCR5 were achieved with AZD5672 as confirmed
by an ex vivo pharmacodynamic assay. This study is in line with
similar studies using maraviroc and SCH351125, suggesting that
CCR5 antagonism alone is unlikely to be a viable therapeutic strat-
egy in rheumatoid arthritis.21

J. G. Cumming et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1655–1659
1659
Table 3
2. Katschke, K. J.; Rottman, J. B.; Ruth, J. H.; Qin, S.; Wu, L.; LaRosa, G.; Ponath, P.;
Park, C. C.; Pope, R. M.; Koch, A. E. Arthritis Rheum. 2001, 44, 1022.
3. Vierboom, M. P. M.; Zavodny, P. J.; Chou, C.-C.; Tagat, J. R.; Pugliese-Sivo, C.;
Strizki, J.; Steensma, R. W.; McCombie, S. W.; Çelebi-Paul, L.; Remarque, E.;
Jonker, M.; Narula, S. K.; Hart, B. Arthritis Rheum. 2005, 52, 627.
4. Prahalad, S. Genes Immun. 2006, 7, 264.
5. (a) Lemoine, R. C.; Wanner, J. Curr. Top. Med. Chem. 2010, 10, 1299; (b) Palani,
A.; Tagat, J. R. J. Med. Chem. 2006, 49, 2851; (c) Xue, C.-B.; Chen, L.; Cao, G.;
Zhang, K.; Wang, A.; Meloni, D.; Glenn, J.; Anand, R.; Xia, M.; Kong, L.; Huang, T.;
Feng, H.; Zheng, C.; Li, M.; Galya, L.; Zhou, J.; Shin, N.; Baribaud, F.; Solomon, K.;
Scherle, P.; Zhao, B.; Diamond, S.; Emm, T.; Keller, D.; Contel, N.; Yeleswaram,
S.; Vaddi, K.; Hollis, G.; Newton, R.; Friedman, S.; Metcalf, B. Med. Chem. Lett.
2010, 1, 483; (d) Kazmierski, W. M.; Anderson, D.; Aquino, C.; Chauder, B.;
Duan, M.; Ferris, R.; Kenakin, T.; Koble, C.; Lang, D.; Mcintyre, M.; Peckham, J.;
Watson, C.; Wheelan, P.; Spaltenstein, A.; Wire, M.; Svolto, A.; Youngman, M. J.
Med. Chem. 2011, 54, 3756.
In vivo PK data for selected compounds
a
a
Compds
Species
Cla (mL/min/kg)
Vss (L/kg)
t½ (h)
Fb (%)
1
1
6
6
Rat
Dog
Rat
Dog (M)
Dog (F)
Rat
Dog (M)
Dog (F)
28
18
71
12
7.5
38
15
22
5.3
5.7
7.7
3.2
2.2
5.0
4.5
5.8
2.6
3.9
2.4
8.3
4.7
2.1
3.9
3.8
38
86
7.3
15
22
41
46
51
6
7e
7e
7e
a
Compounds dosed 1–2 mg/kg iv.
Compounds dosed 2–5 mg/kg po.
b
6. (a) Dorr, P.; Westby, M.; Dobbs, S.; Griffin, P.; Irvine, B.; Macartney, M.; Mori, J.;
Rickett, G.; Smith-Burchnell, C.; Napier, C.; Webster, R.; Armour, D.; Price, D.;
Stammen, B.; Wood, A.; Perros, M. Antimicrob. Agents Chemother. 2005, 49,
4721; (b) Wood, A.; Armour, D. Prog. Med. Chem. 2005, 43, 239; (c) Price, D. A.;
Armour, D.; de Groot, M.; Leishman, D.; Napier, C.; Perros, M.; Stammen, B. L.;
Wood, A. Bioorg. Med. Chem. Lett. 2006, 16, 4633; (d) Armour, D. R.; de Groot, M.
J.; Price, D. A.; Stammen, B. L. C.; Wood, A.; Perros, M.; Burt, C. Chem. Biol. Drug
Des. 2006, 67, 305.
7. (a) 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; (b)
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; (c) Cumming, J. G.; Brown, S. J.; Cooper, A. E.; Faull, A. W.; Flynn, A. P.;
Grime, K.; Oldfield, J.; Shaw, J. S.; Shepherd, E.; Tucker, H.; Whittaker, D. Bioorg.
Med. Chem. Lett. 2006, 16(13), 3533.
Table 4
Additional data for compound 7e (AZD5672)
Chemotaxis IC50
Whole blood activity A2
pKa
Human plasma protein binding
Aqueous solubility pH7.4
CYP1A1, CYP2C9, CYP2C19 IC50
CYP2D6 IC50
CYP3A4 IC50
Caco2 A-B/B-A Papp @ 10
Caco2 A–B/B–A Papp @ 100
0.69 nM
0.76 nM
8.4
92%
2700
>50
23
lM
l
M
l
M
9 lM
l
M
0.7/9.2 cm/s ꢁ 10ꢂ6
8. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. J. Med. Chem. 2006, 49, 5029.
9. Shamovsky, I.; Connolly, C.; David, L.; Ivanova, S.; Nordén, B.; Springthorpe, B.;
Urbahns, K. J. Med. Chem. 2008, 51, 1162.
lM
1.4/11 cm/s ꢁ 10ꢂ6
10. Dragic, T.; Trkola, A.; Thompson, D. A. D.; Cormier, E. G.; Kajumo, F. A.;
Maxwell, E.; Lin, S. W.; Ying, W.; Smith, S. O.; Sakmar, T. P.; Moore, J. P. Proc.
Natl. Acad. Sci. U.S.A. 2000, 97, 5639.
11. Finke, P. E.; Meurer, L. C.; Oates, B.; Budhu, R. J.; Mills, S. G.; MacCross, M.;
Malkowitz, L.; Springer, M. S.; Daugherty, B. L.; Gould, S. L.; DeMartino, J. A.;
Siciliano, S. J.; Carella, A.; Carver, G.; Holmes, K.; Danzeisen, R.; Hazuda, D.;
Kessler, J.; Lineberger, J.; Miller, M.; Schleif, W. A.; Emini, E. A. Bioorg. Med.
Chem. Lett. 2001, 11, 265.
12. Lynch, C. L.; Willoughby, C. A.; Hale, J. L.; Holson, E. J.; Budhu, R. J.; Gentry, A. L.;
Rosauer, K. G.; Caldwell, C. G.; Chen, P.; Mills, S. G.; MacCross, M.; Berk, S.;
Chen, L.; Chapman, K. T.; Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino,
J. A.; Siciliano, S. J.; Cascieri, M. A.; Carella, A.; Carver, G.; Holmes, K.; Schleif, W.
A.; Danzeisen, R.; Hazuda, D.; Kessler, J.; Lineberger, J.; Miller, M.; Emini, E. A.
Bioorg. Med. Chem. Lett. 2003, 13, 119.
Table 5
Cardiac safety margins for compound 7e (AZD5672) vs 1
1
7e
Whole blood activity A2
1.1 nM
1.9
0.76 nM
11 lM
8% free
0.4 mg/kg
2.3 nM
1.8 nM
6400
hERG electrophysiology IC50
Human plasma protein binding
Predicted once daily human dose
Target total hu Cmin at steady state
Predicted free hu Cmax at steady state
Margin hERG/free hu Cmax
l
M
18% free
0.6 mg/kg
3.4 nM
7.5 nM
250
13. (a) Tucker, H. WO 2003042205; Chem. Abstr. 2003, 138, 385314.; (b) Tucker, H.
WO 2006001751; Chem. Abstr. 2006, 144, 108212.
14. For experimental procedures see Ref. 13
15. Springthorpe, B.; Strandlund, G. WO 2005037052; Chem. Abstr. 2005, 142,
426388.
Acknowledgments
16. Seglan, P. O. Methods Cell Biol. 1976, 13, 29.
The authors would like to thank our colleagues Lucy Ashman,
Susan Mellor and Lorraine Newboult for developing and carrying
out the biological assays and Ken Grime, Anthony Atkinson, Kerry
Frost and Deborah Westfield for providing the PK data.
17. Leach, A. G.; Jones, H. D.; Cosgrove, D. A.; Kenny, P. W.; Ruston, L.; MacFaul, P.;
Wood, J. M.; Colclough, N.; Law, B. J. Med. Chem. 2006, 49, 6672.
18. Waring, M.; Johnstone, C. Bioorg. Med. Chem. Lett. 2007, 17, 1759.
19. Waring, M. Bioorg. Med. Chem. Lett. 2009, 19, 2844.
20. An improved route was developed for multikilogram manufacture of AZD5672,
see: Brock, S.; Hose, D. R.; Moseley, J. D.; Parker, A. J.; Patel, I.; Williams, A. J.
Org. Proc. Res. & Dev. 2008, 12, 496.
References and notes
21. Gerlag, D. M.; Hollis, S.; Layton, M.; Vencovsky, J.; Szekanecz, Z.; Braddock, M.;
Tak, P. P. Arthritis Rheum. 2010, 62, 3154.
1. Haringman, J. J.; Smeets, T. J. M.; Reinders-Blankert, P.; Tak, P. P. Ann. Rheum.
Dis. 2006, 65, 294.