Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin

Article abstract of DOI:10.1016/j.bmcl.2013.12.101

β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem's activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.

Full text of DOI:10.1016/j.bmcl.2013.12.101

Bioorganic & Medicinal Chemistry Letters 24 (2014) 780–785
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of MK-7655, a b-lactamase inhibitor for combination
with PrimaxinÒ
a
a
a
a
a
Timothy A. Blizzard a, , Helen Chen , Seongkon Kim , Jane Wu , Rena Bodner , Candido Gude ,
Jason Imbriglio a, Katherine Young b, Young-Whan Park b, Aimie Ogawa b, Susan Raghoobar b,
Nichelle Hairston b, Ronald E. Painter b, Doug Wisniewski b, Giovanna Scapin a, Paula Fitzgerald a,
Nandini Sharma a, Jun Lu a, Sookhee Ha a, Jeff Hermes b, Milton L. Hammond a,b
⇑
a Department of Medicinal Chemistry, Merck Research Labs, Rahway, NJ 07065, USA
b Department of Infectious Diseases, Merck Research Labs, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared
and evaluated as potential partners for combination with imipenem to overcome class A and C b-lacta-
mase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C
b-lactamases in vitro. It effectively restored imipenem’s activity against imipenem-resistant Pseudomonas
and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and PrimaxinÒ is
currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 4 November 2013
Revised 20 December 2013
Accepted 24 December 2013
Available online 3 January 2014
Keywords:
b-Lactamase inhibitor
MK-7655
Antibacterial
Imipenem
Antibiotic
Beta-lactam antibiotics have played a key role in the treatment of
bacterial infections for over half a century.1 Carbapenems, a subset
of beta-lactam antibiotics, have been especially important for treat-
ment of serious nosocomial infections.2 One of the most important
carbapenems is Merck’s PrimaxinÒ, a combination of the carbape-
nem antibiotic imipenem and the renal DHP inhibitor cilastatin.
b-lactamases, divided into four broad classes (A, B, C, and D) based
on their structures.4 A proven strategy to restore antibacterial
activity is to add a b-lactamase inhibitor (BLI) to the antibiotic.5,6
For example, the class A b-lactamases responsible for resistance
of Gram-positive bacteria to amoxicillin can be inhibited by clavu-
lanic acid. Addition of clavulanic acid to amoxicillin successfully
restores the original spectrum of amoxicillin. In recent years some
strains of Gram-negative bacteria, especially Pseudomonas aerugin-
osa and Klebsiella pneumoniae, have developed imipenem resis-
tance mediated by class C (e.g. ampC)7 and class A (e.g. KPC-2)8
b-lactamases, respectively.9 In order to overcome this resistance,
we began a program aimed at discovering a class A/C BLI for com-
bination with PrimaxinÒ. We report herein the discovery of MK-
7655, the clinical candidate that resulted from this program.
We have previously reported the discovery of MK-8712, a
bridged monobactam BLI that is effective against class C b-lacta-
mases (e.g. ampC) but not the class A KPC enzymes.10,11
NH
H
N
H
OH
HN
H
H
N
H
S
O
S
O
+
O
OH
OH
O
NH2
CO2H
imipenem
cilastatin
Beta-lactams kill bacteria by inhibiting the cell wall construc-
tion enzymes known as PBPs. However, some bacteria have devel-
oped enzymes that can destroy beta-lactams before they can
inactivate the PBPs. These enzymes, known as b-lactamases, thus
enable the bacteria to survive even in the presence of high concen-
trations of beta-lactams.3 There are hundreds of known
+H2N
O
O
H2N
N
N
H
N
H
H
N
N
-
O
SO3
O
OSO3H
MK-8712
NXL-104
⇑
Corresponding author.
E-mail address: timblizzard@comcast.net (T.A. Blizzard).
0960-894X/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.12.101

T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 24 (2014) 780–785
O
781
The development of MK-8712 was discontinued due, in part, to
N
O
its lack of class A b-lactamase coverage and we turned our atten-
tion to the discovery of class A/C dual inhibitors. We pursued sev-
eral leads including de novo design and modification of existing
BLIs. One very promising lead series was the bridged bicyclic urea
BLIs discovered at Sanofi-Aventis.12 This series included a clinical
candidate, NXL 104, which is currently in development by Astra
Zeneca in combination with ceftazidime.13 Although this series is
much more synthetically challenging than the bridged monobac-
tams, it has the advantage of being active against both class A
and class C b-lactamases. Based on our experience in the monobac-
tam series, we decided to examine a series of bridged bicyclic ureas
with basic heterocyclic side chains.
HO
N
H
N
a
N
+
H
N
H
N
NH2
N
O
OCH2Ph
O
OCH2Ph
19
24
25
N
O
N
N
O
N
H
N
H
b
c
N
H
H
N
N
O
OH
O
OSO3Na
6
26
The (S)-azepine side chain of MK-8712 was attached to the
bicyclic urea core, as outlined in Scheme 1. Starting with the
known acid 19,14 amide formation with amine 20 afforded the pro-
tected amide 21. Deprotection of the benzyl ether followed by sul-
fation and BOC removal afforded the (S)-azepine analog 1.
The (R) azepine analog 2, the piperidine analog 3, and the iso-
meric pyrrolidine analogs 4 and 5 were prepared by analogous
routes using the appropriate protected amines as starting materials.
The N-methyl piperidine analog 6 was synthesized from acid 19
as outlined in Scheme 2. Acylation of 19 with amine 24 followed by
debenzylation and sulfonylation afforded the desired N-methyl
analog 6 in good overall yield.
Scheme 2. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH2Cl2, 50 °C, 1 h, 84%; (b) 10% Pd/C, H2, CH3OH, 25 °C, 99% crude; (c) SO3Ápyridine
complex, pyridine, 25 °C, 31%.
O
O
O
S
O
O
HO
N
H
O
+
S
a
N
H
N
H
N
NH2
N
O
OCH2Ph
O
OCH2Ph
19
27
28
The corresponding sulfone analog 7 which has a neutral side
chain, in contrast to analogs 1–6 which have side chains that
would be positively charged at physiological pH, was similarly pre-
pared as summarized in Scheme 3. BOP15 mediated acylation of
aminosulfone 27 with acid 19 afforded the intermediate amide
28. Debenzylation of 28 followed by sulfation of the free hydroxyl
group afforded the desired sulfone 7.
O
O
O
S
O
N
O
S
O
N
H
N
H
b
c
N
H
H
N
N
O
OH
O
OSO3Na
7
29
The para-substituted pyridine 8 was prepared via the synthetic
route outlined in Scheme 4. Coupling of acid 19 and 4-amino-pyr-
idine 30 afforded the protected amide 31. Protecting group re-
moval followed by sulfation with sulfur trioxide pyridine
complex afforded the para-pyridyl analog 8.
The meta-pyridyl analog 9 and the ortho-pyridyl analog 10 were
synthesized via analogous routes from the appropriate aminopyri-
dines. Although analogs 8–10 have weakly basic side chains, the
side chains would be neutral at physiological pH.
Scheme 3. Reagents and conditions: (a) BOP, Hunig’s base, DMF, 25 °C, 1 h 77%; (b)
Pd/C, H2, CH3OH, 25 °C, 99% crude; (c) SO3Ápyridine complex, pyridine, 25 °C, 15%.
O
N
O
HO
N
N
H
a
N
H
+
N
H
NH2
N
N
30
O
OCH2Ph
O
OCH2Ph
18
31
O
N
O
BOC
N
O
HO
a
N
N
N
N
H
+
H
H
b
c
N
N
H
NH2
N
H
N
O
OCH2Ph
N
19
20
O
OSO3H
OH
O
32
8
BOC
BOC
N
N
O
O
Scheme 4. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH2Cl2, 50 °C, 1.5 h, 68%; (b) 10% Pd/C, H2, CH3OH, CH2Cl2, 25 °C, 47%; (c)
SO3Ápyridine complex, pyridine, 25 °C, 47%.
N
H
N
H
b
N
N
N
H
H
N
O
OCH2Ph
O
OH
21
22
The 6-aminopyridine analog 11 was targeted since the side
chain would be more basic (due to electron donation by the second
ortho nitrogen) than the unsubstituted pyridines in analogs 8–10,
although it would likely not be protonated at physiological pH (cal-
culated pKa 4.7 for 11 vs 3.6 for 9). Analog 11 was prepared as out-
lined in Scheme 5. Acylation of the core acid 19 with protected
aminopyridine 33 afforded amide 34 in modest yield. Debenzyla-
tion followed by sulfation and BOC removal afforded the desired
aminopyridyl analog 11 in low overall yield. In order to probe
the effect of a positively charged aromatic side chain, the amino-
methylpyridine analog 12 was prepared in a similar manner by
substituting 4-BOC-aminomethylpyridine for 33.
H
BOC
N
N
O
O
N
H
N
H
c
d
N
N
N
H
H
N
-
OSO3H
OSO3
Bu4N+
O
O
1
23
Scheme 1. Reagents and conditions: (a) EDC, HOBT, Et3N, CH2Cl2, 25 °C, 56%; (b)
Pd/C, H2, CH3OH, 25 °C; (c) SO3Ápyridine complex, pyridine, Bu4NSO3H, 25 °C; (d)
TFA, CH2Cl2, 33% over three steps.

782
T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 24 (2014) 780–785
O
A ‘hard quat’ analog, 13, with an N-methylpyridinium side chain
I-
N+
O
that would be positively charged at all pHs, was also targeted. It
was prepared in a straightforward manner but very poor overall
yield from acid 19 and aminopyridine 37 as outlined in Scheme 6.
To determine the effect of a negatively charged (at physiological
pH) side chain, the carboxylic acid analog 14 was targeted. Amida-
tion of acid 19 with protected aminobenzoic acid 40 proceeded in
very good yield to afford amide 41. Debenzylation proceeded
smoothly but sulfation and cleavage of the t-butyl ester formed
14 in disappointingly low overall yield (Scheme 7).
To complement the positively and negatively charged side chain
analogs, one analog with a zwitterionic side chain was also tar-
geted. Amino acid 15 was synthesized from acid 19 and the bis-
protected aminophenylalanine 44 as outlined in Scheme 8.
The effect of a slightly longer spacer between the bicyclic core
and the side chain was probed by the extended analog 16, in which
a methylene spacer has been inserted between the core amide and
the piperidine ring of 3. The synthesis of 16 was relatively straight-
forward, as outlined in Scheme 9, and proceeded in good overall
yield.
To further probe the effect of modification of the amide linker of
3, the N-methyl amide 17 was prepared (Scheme 10). Since the
desired BOC-protected starting material was not available com-
mercially, it was necessary to use the corresponding CBZ-protected
analog 52 instead and switch protecting groups during the deben-
zylation step. Thus, amide coupling of core acid 19 and amine 52
afforded amide 53 in good yield. Debenzylation of 53 in the
presence of BOC-anhydride resulted in in situ protection of the
intermediate free piperidine nitrogen to provide the desired BOC-
protected intermediate 54 which was then converted to 17 by
our usual protocol.
HO
N+
N
H
a
N
+
H
N
H
NH2
N
N
37
O
OCH2Ph
O
OCH2Ph
19
38
N+
O
N+
O
N
N
H
b
c
N
H
H
N
H
OH
N
N
-
O
OSO3
O
39
13
Scheme 6. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH3CN, 60 °C, 1 h, 29%; (b) 10% Pd/C, H2, CH3OH, 25 °C, 100% crude; (c) SO3Ápyridine
complex, pyridine, 25 °C, 5%.
OtBu
O
HO
O
a
+
N
H
NH2
OtBu
N
40
O
OCH2Ph
19
OtBu
O
O
O
O
N
H
N
H
b
N
N
N
H
H
N
O
OCH2Ph
O
OH
42
41
OtBu
OH
O
O
O
O
Finally, the ester-linked analog 18 was prepared by substitution
of 4-hydroxy-BOC-piperidine for amine 48 in the synthetic route
outlined in Scheme 9.
N
H
N
H
N
N
H
H
c
d
N
N
All compounds were evaluated in an enzyme inhibition assay
and in an in vitro synergy assay (Table 1). The enzyme assay mea-
sured the compound’s ability to inhibit the hydrolysis of nitrocefin
by four b-lactamases (one class A BL, two class C BLs, and one class
D BL), reported as an IC50 (nM).16 The synergy assay measured the
compound’s ability to reduce the MIC of imipenem against
clinically relevant b-lactamase producing strains of Pseudomonas,
Klebsiella, and Acinetobacter. The synergy data in Table 1 is reported
O
OSO3H
O
OSO3H
14
43
Scheme 7. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH2Cl2, 50 °C, 1 h, 75%; (b) 10% Pd/C, H2, CH3OH, 25 °C, 96% crude; (c) SO3Ápyridine
complex, pyridine, 25 °C; (d) TFA, CH2Cl2, 4% over two steps.
as the concentration (
MIC for each strain to 4
l
M) of BLI required to reduce the imipenem
g/mL.16
l
We were pleased to find that a wide variety of heterocyclic side
chains were tolerated and that many of the new compounds had
excellent activity against class A and class C b-lactamases (Table 1).
For example, the piperidine analog 3 inhibits both KPC-2, a key
class A enzyme responsible for carbapenem resistance in Klebsiella
pneumoniae, and AmpC, the enzyme responsible for resistance in
Pseudomonas. It is less effective against AmpC from Acinetobacter
species and is ineffective against the class D enzyme Oxa-40, also
from acinetobacter. However, resistant Acinetobacter accounts for
only a very small percentage of clinical cases and is much less
important than Pseudomonas and Klebsiella. Piperidine 3 also effec-
tively synergized imipenem against imipenem-resistant Klebsiella
and Pseudomonas, with concentrations of 12.5 and 4.7 micromolar,
O
HO
a
+
N
BOC
H
N
H
N
NH2
N
O
OCH2Ph
33
19
O
O
BOC
BOC
N
H
N
N
H
N
H
N
N
H
b
N
N
N
H
H
N
O
OCH2Ph
O
OH
35
34
respectively, reducing the imipenem MIC to 4 lg/mL.
O
O
An X-ray crystal structure of 3 bound in the active site of AmpC
(Pseudomonas) confirmed the assigned structure of 3 and provided
insights into its key interactions with the enzyme (Fig. 1; coordi-
nates for the structure have been deposited with the Protein Data
Bank, entry 4NK3). As expected, 3 binds to AmpC in a very similar
manner to our previous BLI MK-8712.10
BOC
c
H2N
d
N
N
H
N
N
N
H
H
N
N
H
H
N
N
O
OSO3H
O
OSO3H
11
36
The seven and five membered ring analogs (1–2 and 4–5,
respectively) demonstrated comparable activity in both the
enzyme and synergy assays.
Scheme 5. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH2Cl2, 50 °C, 2.5 h, 50%; (b) 10% Pd/C, H2, CH3OH, 25 °C, 100% crude; (c)
SO3Ápyridine complex, pyridine, 25 °C; (d) TFA, CH2Cl2, 10% over two steps.

T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 24 (2014) 780–785
783
O
O
H
N
BOC
+
OtBu
O
HO
CBZ
a
N
N
+
H
OCH2Ph
HO
a
N
N
H
N
H
O
NH2
O
19
52
N
44
O
OCH2Ph
19
BOC
HN
O
H
N
CBZ
BOC
N
O
N
O
OtBu
BOC
OtBu
N
N
O
b
O
O
N
N
H
H
N
N
N
N
H
H
b
O
OCH2Ph
O
OH
N
N
53
54
H
N
OCH2Ph
H
N
O
O
OH
O
O
46
45
BOC
H
N
HN
H2N
N
O
BOC
OtBu
OH
N
N
c
d
O
O
N
N
N
H
H
N
N
H
N
H
O
OSO3H
O
OSO3H
N
N
H
H
c
d
17
55
N
N
O
OSO3H
O
OSO3H
15
47
Scheme 10. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide,
Et3N, CH2Cl2, 50 °C, 1 h, 68%; (b) 10% Pd/C, H2, BOC-anhydride, CH3OH:THF (2:1),
25 °C; (c) SO3Ápyridine complex, pyridine, 25 °C; (d) TFA, CH2Cl2, 2 h, 0 °C, 5% over
two steps.
Scheme 8. Reagents and conditions: (a) 2-chloro-N-methylpyridinium iodide, Et3N,
CH2Cl2, 50 °C, 1 h, 81%; (b) 10% Pd/C, H2, CH3OH, 25 °C; (c) SO3Ápyridine complex,
pyridine, 25 °C; (d) TFA, CH2Cl2, 6% over three steps.
sulfone 7, we believe the observed lack of synergy for pyridine ana-
log 8 may also be due to increased efflux since the side chain nitro-
gen would not be protonated at physiological pH. Indeed, addition
of a basic nitrogen to to the aromatic side chain, as in the methyl-
amino analog 12, does improve synergy, but not to an extent com-
mensurate with the increased enzyme inhibitory activity. In fact,
even the most potent b-lactamase inhibitors required a concentra-
O
HO
a
NH2
+
N
N
H
BOC
N
48
O
OCH2Ph
BOC
19
N
tion of ꢀ3
lM or greater to synergize imipenem to 4 lg/mL. This
O
observed activity ‘floor’ is most likely due to a combination of
not only the inherent potency of the compound, but also the con-
centration of enzyme in the bacterial cell and the turnover number
for effective inhibition (both MK-7655 and avibactam are revers-
ible covalent inhibitors). Attempts to improve synergy by lowering
the pKa of the pyridine side chain by incorporating an electron
donating nitrogen (as in analog 11) were unsuccessful. Analog 11
(and similar analogs which are not shown in Table 1) retained
excellent enzyme inhibitory activity but were not active in the syn-
ergy assay. Interestingly, the ‘hard quat’ analog 13 was much less ac-
tive than the other aromatic analogs in the enzyme inhibition assay.
The carboxylic acid analog 14, with a side chain that would be
negatively charged at physiological pH, exhibited excellent en-
zyme inhibitory activity but was essentially inactive in the synergy
assay. Similarly, the zwitterionic amino acid analog 15 was a very
effective b-lactamase inhibitor but did not effectively synergize
imipenem against resistant bacteria. It is unclear if the reduced
cellular activity of 14 and 15 is due to poor penetration into the
bacterial cell or due to efflux.
O
N
H
b
N
H
N
N
H
BOC
N
N
H
N
O
OCH2Ph
49
O
OH
50
BOC
N
H
N
O
O
N
H
N
H
c
d
N
N
H
H
N
N
O
OSO3H
O
OSO3H
16
51
Scheme 9. Reagents and conditions: (a) EDC, 4-DMAP, CH2Cl2, 25 °C, 67%; (b) 10%
Pd/C, H2, CH3OH, 25 °C; (c) SO3Ápyridine complex, pyridine, 25 °C; (d) TFA, CH2Cl2,
36% over three steps.
Alkylation of the piperidine nitrogen analog (e.g. N-methyl ana-
log 6), had little, if any, effect on enzyme activity and synergy.
Replacement of the piperidine nitrogen with a sulfone group
(analog 7) resulted in a significant improvement in b-lactamase en-
zyme inhibition but a substantial loss of synergistic activity with
imipenem. This is consistent with our previous observation, during
the course of our work on MK-8712, that a positive charge in the side
chain was essential for prevention of efflux from the bacterial cell.
Interestingly, replacement of the piperidine side chain with
aromatic side chains also resulted in a significant increase in
enzyme inhibition but a decrease in synergy with imipenem. For
example, the pyridine analog 8 had a nearly 80-fold improvement
in its AmpC IC50 but was about five-fold less effective in restoring
imipenem’s activity against pseudomonas. As noted above for
Insertion of a methylene unit between the heterocycle and the
core (analog 16) improved enzyme activity but not synergy with
imipenem, possibly due to increased lipophilicity which we believe
would increase susceptibility to efflux. Alkylation of the amide
nitrogen linker, as in the N-methyl analog 17, however, resulted
in a substantial loss of enzyme inhibition. We also found that
replacement of the amide linker with an ester (analog 18) resulted
in improved enzyme activity without significant loss of activity in
the synergy assay. However, due to the presumably better in vivo
stability of the amide, we focused our effort on the amide series.
The piperidine analog 3 in combination with imipenem had
excellent activity against an extended panel of resistant Pseudomo-
nas aeruginosa and Klebsiella pneumoniae clinical isolates.17 In

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T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 24 (2014) 780–785
Table 1
SAR of bridged bicyclic urea b-lactamase inhibitors
R
Enzyme inhibition (IC50, nM)
In vitro synergy BLI (
lM) to reduce IPM MIC to 4
l
g/mL
KPC-2
AmpC
P. aerug.
69
AmpC
A. baum.
1700
Oxa40
CL 6569
K. pneum.
12.5
CL 5701
P. aerug.
6.25
CL 6188
N
H
#
N
O
OSO3H
R
K. pneum.
A. baum
>50,000
A. baum.
H
N
O
1
245
>100
N
H
H
H
N
O
2
3
225
210
520
465
1200
4100
>50,000
>50,000
12.5
12.5
6.25
4.7
>100
>100
N
H
O
N
N
H
O
N
H
H
4
5
410
260
140
5600
>50,000
>50,000
6.25
6.25
3.12
6.25
>100
>100
N
H
O
N
1900
27,000
N
H
H3C
O
N
6
7
240
150
500
9.5
2700
470
>50,000
>50,000
12.5
50
12.5
50
>100
>100
N
H
O
O
O
N
S
N
H
O
8
9
54
42
36
11
42
260
6
1050
1,200
23
20,000
20,000
530
50
25
>100
>100
>100
>100
>100
>100
N
H
O
N
37
1.2
8
50
100
12.5
50
N
H
O
10
11
12
13
100
25
N
N
H
O
100
360
H2N
H2N
N
N
H
O
3
26
4400
12.5
25
6.25
25
N
N
H
N+
O
210
12,000
>50,000
N
H
O
HO
O
14
15
10
3
11
11
460
4800
>100
50
50
25
>100
>100
N
H
H2N
HO
O
1100
28,000
O
N
H

T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 24 (2014) 780–785
785
Table 1 (continued)
R
Enzyme inhibition (IC50, nM)
In vitro synergy BLI (lM) to reduce IPM MIC to 4
l
g/mL
KPC-2
AmpC
AmpC
Oxa40
CL 6569
CL 5701
CL 6188
N
H
#
N
O
OSO3H
R
K. pneum.
P. aerug.
A. baum.
A. baum
K. pneum.
P. aerug.
A. baum.
O
16
77
30
2200
>50,000
6.25
6.25
>100
N
H
HN
H
O
N
17
2500
9
290
170
2100
1100
>50,000
13,000
50
25
>100
>100
N
CH3
H
N
O
18
6.25
6.25
O
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Figure 1. X-ray crystal structure of 3 in AmpC from Pseudomonas.
addition, it also had pharmacokinetics that were well matched
with those of imipenem, an essential property for a combination
product.18 Finally, 3 was very effective in three mouse models of
infection with clinically relevant imipenem-resistant Pseudomonas
and Klebsiella strains.19
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Based on its superior in vitro and in vivo activity, acceptable PK
and physical properties, and lack of significant off-target activities
or toxicity in preliminary safety testing, 3 was selected for devel-
opment and assigned the development number MK-7655. An im-
proved large scale synthesis of MK-7655 was recently reported
by a Merck Process Chemistry group.20 As of this writing, MK-
7655 has completed phase I clinical trials21 and is currently in
phase II.22 Further developments in this area will be reported in
future communications from this laboratory.
19. Powles, M., Galgoci, A., Misura, A., Liberator, P., Hammond, M. Presented at the
50th ICAAC American Society of Microbiology, Boston, MA, September 2010;
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Presented at the 52nd ICAAC American Society of Microbiology, San Francisco,
CA, September 2012; paper A-009.
22. See clinicaltrials.gov, trial identifier numbers NCT01505634 and NCT01506271.
Acknowledgments
The authors gratefully acknowledge Ian Mangion, Mark Huff-
man, and Rebecca Ruck of the Merck Process Chemistry Depart-
ment for providing a generous supply of the bicyclic core acid 19.