Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.02.016

The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metath

Full text of DOI:10.1016/j.bmcl.2014.02.016

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1820–1824
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure-based design and synthesis of tricyclic IAP (Inhibitors
of Apoptosis Proteins) inhibitors
⇑
Alexander W. Hird , Brian M. Aquila, Michael H. Block, Edward J. Hennessy, Victor M. Kamhi,
Charles A. Omer, Naomi M. Laing, Jamal C. Saeh , Li Sha, Bin Yang
Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the
core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system
and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and
XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibi-
tors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro
drug-like properties.
Received 7 January 2014
Revised 3 February 2014
Accepted 6 February 2014
Available online 24 February 2014
Keywords:
Inhibitors of Apoptosis Proteins
Ó 2014 Elsevier Ltd. All rights reserved.
XIAP
cIAP
Smac
Structure-based drug design
Ring-closing metathesis
Resistance to programmed cell death is one of the hallmarks of
cancer.1 As such, we became interested in the development of
antagonists of the Inhibitors of Apoptosis (IAP) Protein family.
The family consists of 8 proteins, each of which contains 1–3 bac-
ulovirus IAP repeat (BIR) domains. These proteins are often inhib-
ited by second mitochondria-derived activator of caspases
(SMAC).2 X-chromosome-linked IAP (XIAP) directly binds to
caspases 3,7 and 9, thereby inhibitng apoptosis directly.3 Other
IAP family members may bind to SMAC, thereby preventing its
inhibition of XIAP,4 or regulate other pro-survival proteins, such
as NF-
B.5
At the outset of our reasearch program, several companies and
academic research groups had already published on various SMAC
mimetics as IAP antagonists.5–9
Cyclization of linear molecules is a strategy used to produce
more drug-like compounds; it often reduces the number of
rotatable bonds, which can result in increased potency (reduced
entropic cost) and may also improve permeability through the
j
H
S
Ph
H
N
H
N
N
N
N
N
N
Ph
N
O
H
O
O
CO2
H
O
O
O
O
NH
O
NH
NH
HN
HN
HN
1
2
3
AVPI
Novartis
LBW242
Genentech
Figure 1. AVPI and literature monomeric Smac mimetics.
⇑
Corresponding author. Tel.: +1 781 839 4145; fax: +1 781 839 4650.
E-mail address: alexander.hird@astrazeneca.com (A.W. Hird).
Current address: Novartis, Oncology Translational Medicine, 220 Massachusetts
Ave, Cambridge, MA 02139, United States.
http://dx.doi.org/10.1016/j.bmcl.2014.02.016
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

A. W. Hird et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1820–1824
1821
cyclization between either the P2 and P3 residues, as in compound
2, or P3 and P4 residues, as in compound 3. Replacing the
iso-leucine residue with a capping group has also been reported
to improve cellular potency.11
We considered the overlay of molecules such as 2 and 3 and de-
signed a series of novel tricyclic compounds derived from a fully
saturated pyrollo[2,3-c]pyridine scaffold. As depicted in Figure 2,
the thioproline ring of 2 overlays well with the pyrrolidine ring
of 3. We elected to retain the pyrrolidine ring in our hybrid com-
pound, 4 (Fig. 3) believing this would allow for more facile synthe-
sis and stereocontrol at the ring junction.12
The synthetic route to compound 4 is shown in Scheme 1.
Known ethyl 6-azaindole-2-carboxylate13 was protected with
Boc2O before subjecting to hydrogenation over catalytic Rh/alu-
mina to yield the all-syn saturated bicycle, 6. Initial attempts at
hydrogenation with other metal catalysts or lower pressure were
not successful.
Protection of the piperidine nitrogen allowed functionaliza-
tion of the ester to yield alkene, 8 via alcohol 7. Boc deprotec-
tion followed by amide coupling with a protected (S)-pentenoic
acid derivative gave the ring-closing metathesis precursor, which
existed as an inseparable 1:1 mixture of diastereomers, 9a and
9b. Ring closure proceeded smoothly with 20 mol % Grubbs’ first
Figure 2. Crystal structure of compound 2 (cyan) bound to a chimeric ML–IAP/XIAP
BIR domain (pdb ID: 2I3I)7 overlaid with docked pose of 3 (green).
elimination of hydrogen bond donors and acceptors.10 A common
theme for many reported SMAC mimetics is conformational
restriction of the critical AVPI motif of SMAC (1, Fig. 1) by
H
S
N
H
H
H
N
Ph
N
N
N
N
N
Ph
H
N
O
O
O
Ph
O
O
O
O
NH
NH
NH
HN
HN
HN
2
3
4
Novartis
LBW242
Genentech
Figure 3. Design of tricyclic inhibitor, 4.
O
O
O
e
f
,
c
a
g
d
,
b
,
z
N
HN
Cb N
N
N
t
Et
OE
O
H
N
H
oc
oc
B
B
-
-
7
5
6
)
)
(
(
H
H
H
i
h
,
N
N
N
z
N
z
Cb
Cb
z
Cb N
N
H
oc
B
O
O
BocHN
BocHN
-
a
9
8
9b
)
(
H
H
H
N
N
N
N
z
Cb
z
Cb
H
O
O
BocHN
BocHN
a
10
10b
H
H
H
H
H
N
NH
N
N
N
m n
,
N
l
k
z
Cb
,
j
a
10
H
O
Ph
O
O
O
N
O
O
NH
NH
NH
N
HN
11
12
4
Boc
Boc
Scheme 1. Synthesis of 4. Reagents and conditions: (a) NaH, DMF; Boc2O (66%); (b) Rh/Al2O3, H2 (200 psi), THF, 50 °C (97%); (c) CbzCl, DCM, Et3N (84%); (d) LiBH4, THF, 55 °C
(95%); (e) Dess–Marin periodinane, DCM (60%); (f) Ph3PMeBr, BuLi, THF (65%); (g) 4 N HCl in dioxane (93%); (h) (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid, EDCÁHCl,
HOBtÁH2O, N-methylmorpholine (81%); (i) 20 mol % Grubbs I, DCM, 40 °C (a: 46%, b: 79%); (j) 4 N HCl in dioxane (89%); (k) (S)-2-(tert-butoxycarbonyl(methyl)amino)
propanoic acid, EDCÁHCl, HOBtÁH2O, N-methylmorpholine (73%); (l) Pd/C, H2, MeOH (83%); (m) BnCHO, NaBH(OAc)3, DCM; (n) 4 N HCl in dioxane (34%, 2 steps).

1822
A. W. Hird et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1820–1824
Table 1
Structure of tricyclic analogs with varying R groups, affinities for cIAP1 and XIAP BIR3 domains, activity in inhibiting cellular proliferation, physical properties and in vitro
pharmacokinetic properties
H
N
N
R
H
cIAP1 BIR3 FP IC50
M)
XIAP BIR3 FP IC50
M)
MDA-MB-231 GI50
M)
HuPPB (%
free)
Aq sol
(lM)
Hu Mic CLint
min/mg)
(lL/
–R
Compound
LogD
O
(
l
(
l
(
l
O
NH
HN
2
3
4
—
—
0.05*
0.027
0.039
0.024
0.035
0.021
0.044
0.070
0.16
0.055
0.036
0.10
0.073
0.037
0.042
0.044
0.089
0.18
0.77*
1.0
0.99
3.1
1.0
1.5
2.0
3.3
9.2
3.0
1.8
2.2
5.2
2.5
3.0
8.3
>10
1.6
3.7
1.3
>10
>10
—
—
—
—
—
—
5.7
51
17
49
48
34
47
47
—
48
47
32
24
6.5
47
18
18
—
>1000
>1000
>1000
—
2.5
1.3
2.2
1.4
1.3
0.9
0.9
1.0
0.2
1.3
1.3
1.6
1.8
2.3
1.0
2.1
1.4
0.9
0.3
À0.2
0.1
32
<4
4.7
<4
<4
<4
<4
<4
—
6.8
6.9
<4
6.6
28
<4
5.2
<4
<4
—
–CH2CH2Ph
–CH2CH2(4-BrPh)
–CH2CH2(2-FPh)
0.32
0.028
0.096
0.12
0.23
0.67
2.6
0.20
0.37
0.31
0.16
0.34
0.26
0.28
0.97
2.5
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
–CH2CH2(4-FPh)
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
—
–CH2CH2(2-OMePh)
–CH2CH2(3-OMePh)
–CH2CH2(4-OMePh)
–CH2CH2(4-OHPh)
–CH2CH2(2-MePh)
–CH2CH2(3-MePh)
–CH2CH2(4-MePh)
–CH2CH2(4-ClPh)
–CH2CH2(3,4-Cl2Ph)
–CH2CH2(4-NO2Ph)
–CH2CH2(4-CF3Ph)
( )-CH2CH(Me)Ph
–CH2CH2(3-indolyl)
0.063
0.29
0.40
0.49
4.5
10
>1000
>1000
—
–CH2CH2(4-Me-5-thiazolyl)
–CH2CH2(2-pyridyl)
–CH2CH2(3,5-Me2-4-
oxazolyl)
—
—
—
—
—
1.9
—
>1000
32
–CH2CH2(5-Me-2-
benzimidazolyl)
–Bn
–CH2CH2CH2Ph
–CH2CH2Cy
–CH2Cy
–CH2i-Pr
–CHPh2
–Bu
–C(O)CH2Ph
–C(O)CHPh2
–C(O)CH(Ph)CH2OCH2CCH
(isomer 1)
2.5
>10
—
—
>1000
1.3
9.1
7.1
33
34
35
36
37
38
39
40
41
42
0.45
1.3
0.32
0.51
2.8
9.5
1.2
0.066
0.37
0.20
>10
>10
>10
>10
>10
>10
>10
0.75
0.94
0.50
>11
>11
1.3
2.0
—
—
—
0.32
3.0
3.7
52
47
49
—
—
4.9
—
66
3.9
14
>1000
—
>1000
—
—
>1000
—
>1000
>1000
>1000
0.8
1.6
1.5
0.9
0.1
2.7
5.0
8.9
—
14
0.4
1.4
0.6
6.5
27
23
43
–C(O)CH(Ph)CH2OCH2CCH
(isomer 2)
0.94
5.7
>11
17
>1000
0.8
8.5
44
45
46
47
48
49
–C(O)Ph
–Cbz
–C(O)OPh
–C(O)NHPh
–SO2CH2Ph
–SO2Ph
>10
0.22
0.052
0.22
2.8
>10
0.37
1.2
6.3
4.8
—
>70
42
51
62
40
20
>1000
>1000
700
>1000
>1000
>1000
À0.4
1.1
0.7
0.6
0.4
0.7
7.05
20
6.3
6.7
25
>0.369
0.91
3.9
>11
—
8.0
6.7
7.1
*
Literature data.7
generation catalyst14 to yield 10a and 10b, which were sepa-
rated by silica gel chromatography. Both diastereomers were ta-
ken on to the final compound;15 10a underwent Boc
deprotection and amide coupling to produce 11. The piperidine
ring was unmasked (12) and underwent reductive amination
with phenylacetaldehyde. Boc deprotection at the N-terminus
yielded the target tricycle 4 in an unoptimized 1% yield over
14 steps.
Encouraged by the initial activity of 4, we also synthesized ring
expanded tricycle, 50 and unsaturated tricycle, 51 (Fig. 4). Both
compounds demonstrated similar activity to 4, both in cIAP1 and
XIAP BIR3 FP assays as well as in cell proliferation assay in the
MDA-MB-231 cell line16 (data not shown). With the preference
H
H
H
H
Gratifyingly, tricycle 4 maintained potency compared to the
bicyclic compounds 2 and 3 (Table 1); all three compounds had
N
N
N
N
27–50 nM against the BIR3 domain of cIAP1 and ꢀ1
lM potency
O
Ph
O
Ph
O
NH
versus the BIR3 domain of XIAP. Additionally, compound 4 pos-
NH
O
sessed excellent free levels, solubility and was stable in the pres-
ence of human liver microsomes (Clint <4 lL/min/mg). These are
likely partly a consequence of the reduced lipophilicity of 4 com-
HN
HN
50
51
pared to 3 (logD = 1.3 and 2.5 respectively).
Figure 4. 8,5,6-Tricyclic, 50 and unsaturated 7,5,6-tricylic, 51.

A. W. Hird et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1820–1824
1823
NH
HN
O
O
O
H
Ph
N
H
H
N
O
O
N
H
N
Ph
a
,
b
O
O
O
N
NH
H
H
oc
B
oc-
oc-
(
)
)
52
42
B
O
5
3
(
54
43
B
55
N
N
Ph
O
O
O
NH
HN
Figure 5. Synthesis of dimeric tricyclic IAP inhibitors, 53 and 55. Reagents and conditions: (a) CuCl, TMEDA, acetone (54%); (b) TFA, CH2Cl2 (92%).
Table 2
Potency and physical chemical properties of dimeric IAP antagonists
Compound
cIAP1 BIR3 FP IC50
(lM)
XIAP BIR3 FP IC50
(
lM)
MDA-MB-231 GI50
(l
M)
HuPPB (% free)
Aq sol (
l
M)
LogD
53
55
0.003
0.003
0.004
0.028
0.010
0.20
5.1
10
>1000
>1000
1.8
1.9
for N-Me alanine at the N-terminus well established in the litera-
ture,11 we decided to focus SAR exploration by modifications to
the C-terminus of compound 4. A representative set of compounds
synthesized and tested are shown in Table 1.
was converted to dimer 53 in a two step sequence involving alkyne
dimerization mediated by CuCl, followed by Boc deprotection with
TFA. The same sequence produced 55 from 54 (Fig. 5).
The dimeric compounds possessed excellent activity in the fluo-
rescence polarization (FP) assays (Table 2). Compound 55 had
activity at the lower limit of the assay in cIAP1, whereas 53 ap-
proached the lower limit of the assay against both cIAP1 and XIAP.
The cell proliferation assay was better able to distinguish the two
isomers, with 53 inhibiting proliferation with GI50 = 10 nM. In
addition, both analogs maintained good free levels and excellent
solubility. In further profiling, compound 53 lacked activity at
Substituted phenethyl compounds were synthesized either by
reductive amination with commercially available aldehydes or by
alkylation with commercially available alkyl bromides under io-
dide catalysis.17 Substitution around the phenyl ring appeared tol-
erated in cIAP1, with ortho- and meta-substitution slightly
preferred over para-subsitution in XIAP (16 and 17 vs 18). Larger
substituents at the para position were less tolerated still in XIAP
(25, 26). A selection of heterocycles did not lead to improvements
in potency, with several more polar heterocycles lacking activity
versus XIAP BIR3. Truncated benzyl derivative, 33 was less potent,
as was elongated derivative 34, suggesting 4 possesses the optimal
linker length. Saturated and substituted alkyl derivatives were also
less active versus cIAP1 and XIAP BIR3 domains (compounds 35–
39). Substitution at the benzyl position led to a slight decrease in
activity (27), although this did suggest some room for modifica-
tion. While linker length was important (4 vs compounds 33, 34),
ethylene linker was not required; phenylacetic acid derivative,
40, and phenyl carbamate, 46, both maintained good potency in
binding and cellular assays. Interestingly, Cbz derivative, 45, also
maintained activity, despite having a 3-atom linker. Urea 47 was
less active, as was benzylsulfonamide, 48.
While multiple substitution patterns were tolerated, we were
not able to further optimize potency of the initial hit 4. However,
as SMAC itself operates as a dimer in binding IAP proteins,2c many
research groups have generated dimeric SMAC mimetics to further
improve potency against IAP and in particular in a cellular set-
ting.18 Encouraged by these results and our own observations,19
we wished to explore dimeric inhibitors. Based on the maintained
poteny of 27 and more facile chemistry with amide derivatives
such as 40, we first synthesized compounds 42 and 43 and were
gratified to see that 42 maintained activity at XIAP, although a
slight loss of activity was seen against cIAP1 and in the cell prolif-
eration assay (Table 1). As expected, stereochemical identity was
important and 43 was less active in all assays.20 Compound 52
the hERG channel (>33
zymes (>20 M against 5 isoforms) and had good stability in the
presence of rat microsomes (CLint = 7 L/min/mg).
lM), did not inhibit cytochrome P450 en-
l
l
While the in vitro profile of 53 appeared promising, progress
with other leads19 meant that we did pursue testing in vivo.
In conclusion, we have shown the synthesis of a novel tricyclic
peptidomimetic core and demonstrated its application to the
design of potent monomeric and dimeric IAP antagonists with
excellent in vitro physical and pharmacokinetic profiles.21
Acknowledgments
We thank Terry MacIntyre, Galina Repik, Haiyun Wang and
David Whitston for conducting the biochemical and cellular assays
described herein.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.
02.016.
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20. Absolute stereochemistry at the mandelic amide stereogenic center was not
determined.
21. There have recently been other reports of different tricyclic IAP inhibitors. See
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