Discovery of MK-8970: An acetal carbonate prodrug of raltegravir with enhanced colonic absorption

Article abstract of DOI:10.1002/cmdc.201402393

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.

Full text of DOI:10.1002/cmdc.201402393

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DOI: 10.1002/cmdc.201402393
Discovery of MK-8970: An Acetal Carbonate Prodrug of
Raltegravir with Enhanced Colonic Absorption
Abbas M. Walji,*[a] Rosa I. Sanchez,[b] Sophie-Dorothee Clas,[f] Rebecca Nofsinger,[c]
Manuel de Lera Ruiz,[d] Jing Li,[d] Amrithraj Bennet,[e] Christopher John,[f]
David Jonathan Bennett,[a] John M. Sanders,[g] Christina N. Di Marco,[a] Somang Hope Kim,[b]
Jaume Balsells,[d] Scott S. Ceglia,[d] Qun Dang,[a] Kimberly Manser,[c] Becky Nissley,[c]
John S. Wai,[a] Michael Hafey,[b] Junying Wang,[b] Gene Chessen,[f] Allen Templeton,[f]
John Higgins,[f] Ronald Smith,[i] Yunhui Wu,[c] Jay Grobler,[h] and Paul J. Coleman[a]
Developing new antiretroviral therapies for HIV-1 infection
with potential for less frequent dosing represents an important
goal within drug discovery. Herein, we present the discovery of
ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-
1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydro-
pyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly opti-
mized prodrug of raltegravir (Isentress). Raltegravir is a small
molecule HIV integrase strand-transfer inhibitor approved for
the treatment of HIV infection with twice-daily administration.
Two classes of prodrugs were designed to have enhanced co-
lonic absorption, and derivatives were evaluated in pharmaco-
kinetic studies, both in vitro and in vivo in different species, ul-
timately leading to the identification of MK-8970 as a suitable
candidate for development as an HIV therapeutic with the po-
tential to require less frequent administration while maintain-
ing the favorable efficacy, tolerability, and minimal drug–drug
interaction profile of raltegravir.
Introduction
There are an estimated 34 million people living with human
immunodeficiency virus (HIV)-1 worldwide and approximately
2.3 million people are newly infected each year.[1] More than
7.5 million people are on antiretroviral (ARV) therapy globally,
and this number is expected to continue to increase as greater
numbers of patients are diagnosed and therapy initiated.[1,2]
Over the past 15 years, ARV therapy has improved markedly, al-
lowing patients to live longer, making HIV infection a chronic
manageable condition.[3] As a result, the development of new
ARV agents for the treatment of HIV is increasingly being
driven by factors associated with patient compliance (dosing
frequency), safety, and tolerability.[4] Specifically, decreasing the
dosing frequency has been found to have a significant impact
on improving patient adherence.[5]
[a] Dr. A. M. Walji, Dr. D. J. Bennett, C. N. Di Marco, Dr. Q. Dang, Dr. J. S. Wai,
Dr. P. J. Coleman
Department of Medicinal Chemistry, Merck Research Laboratories, Merck &
Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA)
E-mail: abbas_walji@merck.com
[b] Dr. R. I. Sanchez, S. H. Kim, Dr. M. Hafey, J. Wang
Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Merck Research
Laboratories, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA
19486 (USA)
[c] Dr. R. Nofsinger, K. Manser, B. Nissley, Dr. Y. Wu
In 2007,[6] Merck & Co. Inc. introduced raltegravir (RAL; Isen-
tress; 1) as the first HIV-1 integrase strand-transfer inhibitor
(InSTi), thus providing patients with a new first-line ARV agent
as part of highly active antiretroviral therapy (HAART).[7–9] Cur-
rently, RAL is prescribed twice-daily as a 400 mg dose and has
established robust efficacy in treatment-experienced and treat-
ment-na¨ıve patients.[10–13] Furthermore, RAL has maintained an
outstanding five-year safety profile, and minimal drug–drug in-
teractions (DDIs) in extensive clinical evaluations.[14] Based on
the human pharmacokinetic (PK) data and the established
safety profile, we have initiated a phase 3 clinical trial (ON-
CEMRK) to study a higher (1200 mg) once-daily dose.[15] Most
recently, RAL has been approved for the treatment of HIV-1-
infected children and adolescents aged 2–18 years.[16]
Biopharmaceutics, Pharmaceutical Science, Merck Research Laboratories,
Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA)
[d] Dr. M. de Lera Ruiz, Dr. J. Li, Dr. J. Balsells, S. S. Ceglia
Process Chemistry Department, Merck Research Laboratories, Merck & Co.,
Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA)
[e] Dr. A. Bennet
Safety Assessment, Merck Research Laboratories, Merck & Co., Inc., 770
Sumneytown Pike, West Point, PA 19486 (USA)
[f] Dr. S.-D. Clas,+ C. John, G. Chessen, Dr. A. Templeton, Dr. J. Higgins
Discovery Pharmaceutical Sciences, Merck Research Laboratories, Merck &
Co., Inc., 770 Sumneytown Pike, West Point, PA 19486 (USA)
[g] Dr. J. M. Sanders
Computational Chemistry, Merck Research Laboratories, Merck & Co., Inc.,
770 Sumneytown Pike, West Point, PA 19486 (USA)
[h] Dr. J. Grobler
Department of Virology, Merck Research Laboratories, Merck & Co., Inc.,
770 Sumneytown Pike, West Point, PA 19486 (USA)
The success of RAL has sparked significant interest in devel-
oping a once-daily HIV integrase inhibitor.[17] Several ap-
proaches including co-formulation/co-administration with PK
enhancers, reformulation, and medicinal chemistry efforts to-
[i] Dr. R. Smith
Formulation Sciences, Merck Research Laboratories, Merck & Co., Inc., 770
Sumneytown Pike, West Point, PA 19486 (USA)
[+] Current address: PharmaSolv Consulting (Montreal, Canada)
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wards identification of new templates with improved PK prop-
erties have been the major focus.[18] These efforts have provid-
ed several new leads and resulted in the notable discoveries of
elvitegravir (EVG; 2),[19,20] co-formulated with PK enhancer cobi-
cistat, from Gilead Sciences, and dolutegravir (DTG; 3),[21–23] de-
veloped by a Shionogi–ViiV Healthcare–GlaxoSmithKline joint
venture (Scheme 1). Both EVG and DTG have shown similar
was likely associated with low lipophilicity and that the phe-
nolic hydroxy group is significantly ionized at physiological (co-
lonic) pH (cLogD=1.2, pKa =6.7). Based on this hypothesis, we
defined a medicinal chemistry strategy centered on masking
the ionizable phenolic hydroxy group with pro-moieties
known to enhance permeability.[24,31,32] Specifically, we focused
our attention to the acetal carbonyl functionality and divided
our efforts on four subseries (carbonate, ester, carbamate, and
thioester) (Scheme 2). These provided at least two distinct
Scheme 1. Current clinical HIV integrase strand transfer inhibitors.
clinical efficacy with comparable tolerability as RAL.[17] Howev-
er, long-term safety of these new agents is yet to be demon-
strated and continues to be an ongoing subject of clinical re-
search.[14]
Our approach to address the dosing frequency of RAL was
centered on a combined permeability enhancing prodrug[24]
and controlled release formulation strategy,[25] similar to the
discovery of XP13512 for gabapentin.[26–28] RAL has a short
plasma half-life with poor absorption in the lower gastrointesti-
nal tract.[29,30] Therefore, we envisioned a strategy to prolong
plasma exposure of RAL via a prodrug with improved colonic
absorption compared with RAL. The prodrug would be re-
quired to maintain sufficient stability to reach the colon, exhib-
it high colonic permeability, and efficient in vivo conversion to
RAL post-absorption with minimal systemic prodrug circula-
tion. A combined immediate release/controlled release (IR/CR)
formulation was envisioned to achieve exposures that provide
equivalent efficacy to RAL 400 mg twice-daily dose.
Scheme 2. Acetal carbonyl prodrug classes of raltegravir (RAL).
points of chemical diversity (R1 and R2) that could be used to
modulate physicochemical properties.[24]
Chemical synthesis of the prodrugs was initiated from the
potassium salt of RAL using commercially available chloroalkyl
carbonates, or chloroalkyl carbonates synthesized using stan-
dard procedures.[33] In situ generation of the corresponding
alkyl iodides provided a robust chemical method for the prepa-
ration of prodrug 4 (49% yield) and prodrugs 6–9 (Scheme 3).
Prodrug 5 was synthesized in 85% yield using a similar proce-
dure starting with chloromethyl pivalate and sodium iodide as
the iodinating reagent (Scheme 4). The synthesis of prodrug 4
was further optimized to 90% yield, using N,N-diisopropyle-
thylamine (DIPEA) and tetrabutyl ammonium bromide (TBAB)
as the phase-transfer reagent.
Herein, we describe our research efforts that culminated in
the discovery of MK-8970, an optimized acetal carbonate pro-
drug of RAL with enhanced colonic absorption and suitable
physicochemical properties to support development of an IR/
CR formulation for once-daily dosing.
After ensuring adequate chemical stability (>90% remaining
up to four hours at 378C) and sufficient solubility (ꢀ
0.1 mgmLꢁ1) in simulated gastric fluid (SGF) and fasted state si-
mulated intestinal fluid (FaSSIF), we evaluated the metabolic
profiles of the representative prodrugs from each subseries in
hepatocytes from rat, dog and human (Figure 1; data shown
for products 4 and 5 belonging to classes 1 and 2, respective-
ly). In these experiments, we measured the intrinsic clearance
of the prodrug and importantly also followed the appearance
Results and Discussion
Our efforts began with assessing structural features within the
chemical core of RAL that could potentially impair absorption
throughout the gastrointestinal tract. We proposed that the bi-
dentate metal binding pyrimidinone-based pharmacophore
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of RAL to assess the efficiency of
prodrug hydrolysis and confirm
that the major pathway of me-
tabolism in hepatocytes from all
species was conversion to RAL.
Based on these studies, we iden-
tified the acetal carbonate and
acetal ester pro-moieties as the
most promising in terms of effi-
cient conversion to RAL with
minimal unproductive metabo-
lism. Data from these pro-moiet-
ies led to the selection of pro-
drugs 4 and 5 (Scheme 5) as
being representative of classes
1 and 2, and these prodrugs
were moved forward for further
in vitro profiling.
Scheme 3. General chemical synthesis of acetal carbonate prodrugs via the initial (a) and optimized (b) routes. Re-
agents and conditions: a) 18-crown-6, K2CO3, KI, DMF, 49% yield; b) DIPEA, TBAB, DMA, 90% yield.
To follow-up on the metabolic
stability data from hepatocytes,
we evaluated both prodrugs 4
and 5 in S9 intestinal fractions
from rat, dog, and human
(Figure 2). There were no signifi-
cant differences across species in
the rates of conversion to RAL in
the presence and absence of
NADPH, indicating that hydroly-
Scheme 4. General chemical synthesis of acetal ester prodrugs. Reagents and conditions: a) 18-crown-6, K2CO3, NaI,
DMF, 85% yield.
^
Figure 1. Hydrolysis and conversion of a) prodrug 4 and b) prodrug 5 to raltegravir (RAL) in human (~), rat (&) and dog ( ) hepatocyte suspensions.
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In vivo PK results from rat intravenous/oral (i.v./
p.o.) dosing for RAL and prodrugs 4 and 5 are sum-
marized in Table 1. Both acetal carbonate prodrug 4
and acetal ester prodrug 5 displayed rapid clearance
from plasma after i.v. administration, with significant
extrahepatic metabolism as evidenced by plasma
clearances significantly greater than liver blood flow.
The volume of distribution at steady state (Vdss) was
moderate with short half-life. Following p.o. adminis-
tration, low levels of prodrug 4 were detectable at
up to 0.5 hours, while RAL levels were quantifiable at
up to 8 hours. Bioavailability of prodrug 4 was ap-
proximately 1% in rats. The bioavailability of RAL—
relative to i.v. administered RAL—following p.o. ad-
Scheme 5. Summary of the physical properties of prodrugs 4 and 5.
Table 1. Summary of pharmacokinetic data in rat of prodrugs 4 (1 mpk
i.v./10 mpk p.o.) and 5 (1 mpk i.v./5 mpk p.o.).
Prodrug 4
Prodrug 5
Cl [mLminꢁ1 kgꢁ1
]
307ꢂ150
2.2ꢂ1.1
ND
ND
Vdss [Lkgꢁ1
]
T1/2 [h]
0.12ꢂ0.02
0.04
(0.6)[a]
BLQ
Cmax (p.o.) [mm]
Tmax [h]
0.02ꢂ0.01
(2.91ꢂ1.15)[a]
0.5ꢂ0.0
(1.38ꢂ0.63)[a]
ND
(0.5ꢂ0.0)[a]
0.01ꢂ0.01
(3.70ꢂ0.97)
0.001ꢂ0.001
(0.47ꢂ0.12)
0.7ꢂ0.9
p.o. AUC0–24 [mm·h]
(dose [mgkgꢁ1])
p.o. nAUC0–24 [mm·h]
(dose [mgkgꢁ1])
BLQ
(1.17ꢂ0.19)
ND
(0.29ꢂ0.047)
Bioavailability [%]
ND
(47.9ꢂ12.5)[a]
(30ꢂ5)[a]
[a] Data in parenthesis represent values for raltegravir (RAL). Bioavailabil-
ity for RAL was calculated relative to i.v. exposure of 1 administered as
such. Abbreviations: BLQ=below the lower limit of quantification; Cl=
intrinsic clearance;
Cmax =maximum plasma concentration; mpk=
mgkgꢁ1; nAUC=dose-normalized area under the curve; ND=not deter-
mined due to limited concentration data; Tmax =time at which maximum
concentration occurred; Vdss =volume of distribution at steady state.
ministration of prodrug 4 and 5 was 48% and 30%, respective-
ly. These bioavailabilities are similar to the bioavailability of
orally administered RAL, indicating efficient in vivo conversion
of prodrugs 4 and 5 to RAL. For the in vivo PK experiments,
the observed ex vivo instability was minimized by the addition
of 2,2-dichlorovinyl dimethyl phosphate (dichlorvos), an ester-
ase inhibitor, to the blood during sample collection to allow
for accurate quantification of circulating prodrug levels.
Figure 2. Stability of prodrugs a) 4 and b) 5 in human (&), rat (~) and dog
^
(
) S9 intestinal fractions.
The correlative in vitro and in vivo studies in rat provided
the impetus to further explore the structure–activity relation-
ships within these specific prodrug classes (1 and 2) to identify
opportunities for optimization. Ultimately, the best prodrugs
would have to exhibit colonic absorption with consistent in-
creases in RAL plasma concentrations.
sis was the major metabolic pathway for both prodrugs 4 and
5. Further metabolic stability studies were conducted in hep-
arinized plasma to enable in vivo PK experiments. As expected,
the ability of plasma esterases to hydrolyze these prodrugs
varied across species (rat, dog, and human). Both prodrugs 4
and 5 displayed reasonable stability in human and dog
plasma, with significant hydrolysis observed in rat plasma likely
due to the higher esterase capacity (data not shown).
Within the acetal carbonate class, we synthesized analogues
6–9 based on their calculated increases in lipophilicity (mea-
sured using cLogD) and decreases in polar surface area (PSA),
which would be predictive of an increase in permeability. Spe-
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cifically, prodrugs 8 and 9 represent the extremes within the
desired profiles. Methoxyethyl carbonate acetal 8 has the high-
est PSA (184 ꢁ) within the same range of cLogD (2.5) and the
best measured solubility of 0.60 mgmLꢁ1 in FaSSIF. In contrast,
2-methylpropyl isopropyl carbonate acetal 9 has the highest
lipophilicity (cLogD=2.8) with a measurable solubility of
0.04 mgmLꢁ1 in FaSSIF. Prodrugs 6 and 7 fall within a similar
physical property range (FaSSIF solubility: 6=0.06 mgmLꢁ1,
7=0.25 mgmLꢁ1) as prodrug 4, with slightly higher lipophilici-
ty and minor structural changes.
a final candidate based on observed improvements in in vivo
colonic absorption. Several approaches were considered to
achieve >40% colonic absorption within the acetal carbonate
class of prodrugs. However, they were all limited by a lack of
correlation between increased lipophilicity compared with RAL
(Table 2) and relative colonic bioavailability.[34] To evaluate the
extent to which an effective increase in lipophilicity was toler-
ated, the bis-isopropyl analogue 9 was further profiled. Al-
though an improvement was measureable in vitro with 9, a sig-
nificantly lower level of relative colonic bioavailability (10%)
was observed. The increased lipophilicity adversely impacted
solubility, which is essential for colonic absorption, and also en-
hanced other nonproductive metabolic pathways not leading
to RAL (prodrug 9 showed lower in vitro conversion to RAL).
Based on this comparative analysis, we selected acetal carbon-
ate 4 as a final candidate having met the criteria for improved
colonic absorption and exhibited the optimal physical proper-
ties for potential development of a IR/CR-based formulation.
We then tested prodrug 4 in high-dose multi-day oral PK
studies to assess dose proportionality and the level of circulat-
ing prodrug with respect to dose. Based on previous PK stud-
ies with prodrug 4, we expected that the majority of an oral
dose would be converted to RAL and its glucuronide (the
known major metabolic pathway of RAL[36]). Table 3 shows
a comparison of the normalized area under the curve (AUC)
values obtained for RAL after oral administration of prodrug 4,
Upon further formulation and solubility studies, we observed
significant crystallization of prodrug 5 in the standard dosing
vehicles, which limited further studies for direct comparisons.
Based on this result and other solubility studies with related
analogues of acetal ester 5, we chose to limit the optimization
efforts to the acetal carbonate class (1) of prodrugs.
Results from the oral and colonic dog PK studies are sum-
marized in Table 2. Gratifyingly, both prodrugs 4 and 5 showed
at least threefold increases in relative colonic bioavailability,
Table 2. Summary of structure–activity relationship data for prodrugs 4–
9 and raltegravir (RAL).
Compd R1
R2
–
cLogD[a]
Papp
Rel. bioavail.
[%][c]
[b]
[ꢂ10ꢁ6 cmsꢁ1
]
Table 3. Exposures of raltegravir (RAL) following p.o. administration of 4
or RAL (1).
RAL
4
–
1.2
2.5
2.7
2.7
2.7
2.5
2.8
11.6
5.86
11.9
8.9
11.9
1.7
9
40
29
43
31
5
Me Et
Species
Compd
dosed
Dose
(vehicle)
nAUC(0–24 h)
[mm·h] (RAL)
AUC
ratio[a]
5
H
tBu
6
Me iPr
7
Et
Et
Rat
4
4
10 mpk
(80% PEG-400)
5 mpk
0.47ꢂ0.12
3.63ꢂ1.39
0.89
0.98
8
Me CH2CH2OCH3
9
iPr iPr
15.4
10
Dog
(10% Tween80)
[a] Calculated lipophilicity (cLogD); values were calculated using a QSAR
model built from in-house HPLC logD data at pH 7.0. [b] Measured per-
meability (Papp) determined in an LLC-PK1 assay (with cyclosporine A).
[c] Relative dog colonic bioavailability; values are the ratio of AUC0–24 h co-
lonic to AUC0–24 h p.o. administration.
[a] Ratio of the area under the curve (AUC) of RAL from 4/AUC of RAL;
the AUC of RAL was measured from p.o. exposure of RAL administered at
an equivalent dose.
defined as (AUCcolon/AUCoral)ꢂ100, relative to parent compound
1 (9%), with values of 40% and 29% for prodrugs 4 and 5, re-
spectively.
indicating that most of the dose of 4 was converted to RAL in
both rat and dog.
Pharmacokinetic data from the seven-day dose-escalating
p.o. studies in rats and dogs are summarized in Tables 4 and 5.
Data from both species show a highly efficient in vivo enzy-
matic conversion process to generate RAL, while maintaining
low levels (<5%) of circulating prodrug 4 relative to RAL irre-
spective of dose level. Based on the in vitro species compari-
son studies and the PK studies, after a 400 mg dose of prodrug
4, the human exposure of 4 was projected to be <10% of the
total exposure of RAL.
Earlier we presented an analysis of the impact of in vitro sol-
ubility and permeability on in vivo dog colonic absorption for
a series of prodrugs, and lack of correlation between these
data.[34] We recognized the difficulty in using in vitro tools to
predict the extent of dog colonic absorption within this class
of prodrug, and the challenge this presents for the design of
prodrugs with a significant improvement (>40%) of dog co-
lonic absorption. Additionally, the differences in physiology be-
tween the dog and human colonic environments (colonic pH;
transit times) introduce further challenges in directly translat-
ing data from the dog model to the clinic.[35]
Based on these stability, solubility and preclinical PK data,
prodrug 4 met the desired candidate profile and was selected
to move into clinical studies and designated as MK-8970. Pre-
liminary regional absorption studies and evaluation of proto-
type CR formulations in dogs have been completed and will
The lack of predictive in vitro systems to guide lead optimi-
zation, led to a strategy that centered around selection of
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be used to develop prototype formulations to be studied in
preclinical and clinical regional absorption studies.
Table 4. Multi-day dose-escalating pharmacokinetic study in dog. Day 7
exposures of raltegravir (RAL) and 4 following p.o. administration of 4 in
20% PEG400.
Dose
[mpk] measured
Compd
AUC(0–24 h)
[mm·h]
Cmax
[mm]
Tmax
[h]
AUC
[%][b]
Experimental Section
Biological methods
10
10
4
RAL
BLQ[a]
3.42ꢂ0.07
BLQ[a]
0.955ꢂ0.13
BLQ[a]
0.85ꢂ0.15
BLQ[a]
0.84
3.6
In vitro metabolic stability studies: To determine the metabolism of
compounds in hepatocyte suspensions, test compound (prepared
as a 100 mm solution in 1:1 water acetonitrile) was incubated at
a concentration of 1 uM with suspensions of cryopreserved hepa-
tocytes from rat, dog and human subjects at a cell density of 1ꢂ
106 cellsmLꢁ1. The samples were incubated for 0, 5, 15, 30 and
60 min in a 95% humidified incubator at 378C with 5% CO2. At
each time point, the samples were quenched with acetonitrile con-
taining an appropriate internal standard. The samples were then
vortex-mixed and centrifuged at ~2900g for 30 min at 108C. The
supernatants were transferred to clean plates and analyzed using
LC-MS/MS. Rates of prodrug conversion and raltegravir (RAL) for-
mation were determined relative to an appropriate control con-
taining 1 mm prodrug or RAL.
100
100
4
RAL
0.233ꢂ0.07 0.082ꢂ0.017 0.50ꢂ0.25
27.7ꢂ2.96
4.70ꢂ0.59
1.0ꢂ0.0
450
450
4
RAL
2.52ꢂ1.49
70.5ꢂ9.05
1.09ꢂ0.96
8.63ꢂ2.02
2.7ꢂ1.3
1.0ꢂ0.0
[a] BLQ=below limit of quantification. [b] Data represents the area under
the curve (AUC) of 4 as % of RAL AUC.
Table 5. Multi-day dose-escalating pharmacokinetic study in dog. Day 7
exposures of raltegravir (RAL) and prodrug 4 following p.o. administra-
tion of 4 in 10% Tween80.
In vivo pharmacokinetic studies: All animal studies were performed
according to the US National Institutes of Health Guide for the
Care and Use of Laboratory Animals, and experimental protocols
were reviewed by the Merck Institutional Animal Care and Use
Committee (IACUC) (Animal Procedure Statement #090-685-440-
802-85).
Dose
[mpk]
Compd
measured
AUC(0–24 h)
[mm·h]
Cmax
[mm]
Tmax
[h]
AUC
[%][a]
2
2
4
RAL
0.184
5.28
0.189
1.34
0.25
1.0
3.5
2.7
2.6
4.0
20
20
4
RAL
2.8
103
1.85
18.4
0.38
1.5
Intravenous (i.v.)/oral (p.o.) dose pharmacokinetic studies in rats: Test
compound was administered in a suitable vehicle to male Wistar–
Hanover rats. For i.v. administration to rats, a canula implanted in
the jugular vein was used. For p.o. administration, test compounds
were administered by gavage. Blood samples were serially collect-
ed in EDTA-coated tubes containing dichlorvos following dose ad-
ministration for up to 24 h, and plasma was separated by centrifu-
gation. The concentration of test compound in rat plasma was de-
termined by a LC-MS/MS assay following a protein precipitation
step and addition of an appropriate internal standard. Quantifica-
tion was done by determining peak area ratios of the test com-
pound and RAL with respect to the internal standard. PK parame-
ters were obtained using non-compartmental methods (Watson).
The area under the plasma concentration–time curve (AUC0–t) was
calculated from the first time point (0 min) up to the last time
point with measurable test compound concentration using the
linear trapezoidal or linear/log-linear trapezoidal rule. The i.v.
200
200
4
RAL
3.94
149
1.90
37.0
1.0
1.5
750
750
4
RAL
6.34
157
3.35
32.2
1.0
1.5
[a] Data represents the area under the curve (AUC) of 4 as % of RAL AUC.
be communicated shortly. Upon further characterization of the
crystalline form of MK-8970, we identified a more stable poly-
morph, a detailed account of this work will be published in
due course.
MK-8970 (4) is not expected to exhibit direct antiviral poten-
cy due to the prodrug modification that blocks a critical bind-
ing interaction required for strand transfer inhibition. However,
based on the enzymatic cleavage mechanism to release RAL,
we evaluated MK-8970 for antiviral activity in a viral kinetics
assay in the presence of 10% normal human serum. MK-8970
displayed potency (IP=30 nm) similar to that observed with
RAL (IP=14 nm) under identical conditions, which is attributed
to rapid hydrolysis in the presence of human serum.
plasma clearance was calculated by dividing the dose by AUC0–inf
.
The terminal half-life of elimination was determined by unweight-
ed linear regression analysis of the log-transformed data. The time
points for determination of half-life were selected by visual inspec-
tion of the data. The volume of distribution at steady state (Vdss)
was obtained from the product of plasma clearance and mean resi-
dence time (determined by dividing the area under the first
moment curve by the area under the curve). The maximum plasma
concentration (Cmax) and the time at which maximum concentra-
tion occurred (Tmax) were obtained by inspection of the plasma
concentration–time data. Absolute oral bioavailability was deter-
mined from dose-adjusted i.v. and p.o. AUC ratios. To determine
the bioavailability of RAL following administration of prodrug, the
dose-adjusted p.o. AUC was compared with the dose-adjusted
AUC of RAL administered by i.v.
Conclusions
We have identified a novel acetal carbonate prodrug of ralte-
gravir, MK-8970, with improved colonic bioavailability and low
levels of circulating prodrug to provide a new regimen with
potential for QD dosing. MK-8970 exhibits appropriate physico-
chemical properties for development of a combined immedi-
ate release/controlled release (IR/CR) formulation, which could
Oral (p.o.)/colonic dose pharmacokinetic studies in dogs: Six male
beagle dogs (Marshall Farms) weighing 9.0–11.6 kg were used for
the study. Following overnight fasting, dogs were dosed either
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orally (n=3) or colonically via a retrograde catheter method (n=3)
with 4 mgmLꢁ1 solution at 1 mpk of test compound. Dosing was
followed by 5 mL water rinse via oral gavage for oral dosing or
with a post-dose water flush of the catheter for colonic dosing.
Water was restricted for 1 h post dose. Food was returned at 4 h
after dosing. Blood (1 mL) was drawn at pre-dose and 0.25, 0.5, 1,
2, 4, 6, 8 and 24 h post-dosing. The plasma was separated by cen-
trifugation (10 min at 2500 g at 58C) and kept frozen at ꢁ708C
until analysis by LC-MS/MS.
Optimized method using phase-transfer reagent: A mixture of potas-
sium salt of 1[37] (20.0 g, 41.5 mmol), nBu4NBr (14.9 g, 45.6 mmol),
and N,N-diisopropylethylamine (8 mL, 45.8 mmol) in dimethylaceta-
mide (DMA) (100 mL) was heated to 708C. The mixture was then
treated with 1-chloroethyl ethyl carbonate (6.21 mL, 45.6 mmol)
dropwise over 20 min, after which time the reaction was allowed
to stir at 708C overnight. The mixture was cooled to RT and diluted
with EtOAc (120 mL). The solution was washed successively with
water (100 mL) and brine (100 mL). The first aqueous phase was
back extracted with EtOAc (50 mL). The combined organic layers
were washed with water (50 mL), dried over anhydrous Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was crystal-
lized from EtOAc/heptane (2:1) to provide the desired product
(20.9 g, 90%); HPLC: >98% purity (tR =3.89 min; gradient 0.1%
H3PO4/CH3CN, 10!95% over 6 min and hold for 2 min at 95%).
Chemical synthesis
General methods: All solvents used were commercially available
“anhydrous” grade, and reagents were used without purification
unless otherwise noted. Nonaqueous reactions were carried out in
oven- or heat-gun-dried glassware under a N2(g) atmosphere. Mag-
netic stirring was used to agitate the reactions, and they were
monitored for completion by either thin layer chromatography
(TLC) (silica gel 60, Merck) or liquid chromatography–mass spec-
Acetal carbonate prodrugs 6–9 were synthesized according to the
procedure used initially to make prodrug 4, described above.
1-((4-((4-Fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-
oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyri-
midin-5-yl)oxy)ethyl isopropyl carbonate (6): Using initial
method, 1a (1.08 g, 0.0022 mmol) and 1-chloroethyl isopropyl car-
bonate (0.556 g, 0.0033 mmol) gave compound 6 as a white solid
trometry (LCMS).
A Smith Creator microwave from Personal
Chemistry was used for microwave heating, and a CombiFlash
system using RediSep cartridges by Teledyne Isco was used for
silica gel chromatography with fraction collection at 254 nm. Re-
versed-phase HPLC purification was carried out on a Waters HPLC
(XBridge Prep C18 5 mm 19ꢂ150 mm column) using a gradient of
0.1% trifluoroacetic acid in H2O/CH3CN, with sample collection trig-
gered by photodiode array detection. The reported yields are for
isolated compounds of >95% purity, unless otherwise noted, and
were not extensively optimized. Purity analysis was carried out by
HPLC with a Waters 2690 separation module equipped with a YMC
Pro 50ꢂ3 mm i.d. C18 column interfaced with a Waters Micromass
ZMD spectrometer using a gradient of 0.05% trifluoroacetic acid in
1
(0.95 g, 74%); H NMR (400 MHz, CDCl3): d=8.21 (s, 1H), 7.80–7.83
(m, 1H), 7.35–7.39 (m, 2H), 6.99–7.04 (m, 2H), 6.47–6.51 (m, 1H),
4.69–4.75 (m, 1H), 4.58 (d, J=6.0 Hz, 2H), 3.63 (s, 3H), 2.63 (s, 3H),
1.89 (d, J=2.8 Hz, 6H), 1.77 (d, J=5.2 Hz, 3H), 1.21–1.25 ppm (m,
6H); MS (ESI+): m/z 575.2 [M+H]+.
Ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-
1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydro-
pyrimidin-5-yl)oxy)propyl) carbonate (7): Using initial method, 1a
(1.03 g, 0.0021 mmol) and 1-chloropropyl ethyl carbonate
(0.5298 g, 0.0031 mmol) gave compound 7 as a white solid (0.83 g,
1
68%); H NMR (400 MHz, CDCl3): d=8.26 (s, 1H), 7.79–7.82 (m, 1H),
1
H2O/CH3CN with UV detection at 215 and 254 nm. H NMR spectra
7.34–7.37 (m, 2H), 6.98–7.04 (m, 2H), 6.40–6.43 (m, 1H), 4.58 (d,
J=6.0 Hz, 2H), 4.02–4.10 (m, 2H), 3.63 (s, 3H), 2.62 (s, 3H), 2.01–
2.19 (m, 2H), 1.88 (d, J=2.4 Hz, 6H), 1.23 (t, J=7.2 Hz, 3H),
1.06 ppm (d, J=7.2 Hz, 3H); MS (ESI+): m/z 575.0 [M+H]+.
were recorded on a Varian INOVA 400 or 500 MHz spectrometer,
and all chemical shifts (d) are referenced to an internal standard of
tetramethylsilane (TMS) or the residual CDCl3 solvent peak. All tem-
peratures are degrees Celsius unless otherwise noted. Mass spectra
were measured by electrospray ionization (ESI) mass spectroscopy
(MS).
1-((4-((4-Fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-
oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyri-
midin-5-yl)oxy)ethyl (2-methoxyethyl) carbonate (8): Using initial
method, 1a (3.15 g, 0.0065 mmol) and 1-chloroethyl (2-methoxy-
ethyl) carbonate (1.77 g, 0.0097 mmol) gave compound 8 as
Ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-
1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydro-
pyrimidin-5-yl)oxy)ethyl) carbonate (4):
1
a white solid (2.58 g, 67%); H NMR (400 MHz, CDCl3): d=8.17 (s,
Initial method (used also for prodrugs 6–9): A mixture of potassium
salt of 1[37] (31.0 g, 64 mmol), 1-chloroethyl ethyl carbonate
(14.7 mL, 96 mmol), K2CO3 (13.3 g, 96 mmol), KI (13.3 g, 96 mmol),
and 18-crown-6 (0.85 g, 3.2 mmol) in DMF (250 mL) was heated for
about 4 h at 608C. The reaction mixture was then cooled to RT and
diluted with EtOAc (250 mL). The solution was washed successively
with water (250 mL), and brine (200 mL), then dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The resulting
residue was purified using flash chromatography on silica gel (20%
EtOH/EtOAc), and the solid product obtained was further purified
via recrystallization from a mixture of EtOAc/hexane (1:2) to pro-
vide the desired compound as a white solid (17.6 g, 49%);
1H NMR(500 MHz, [D6]DMSO): d=9.92 (s, 1H), 8.75 (t, J=6.2 Hz,
1H), 7.38 (dd, J=8.3, 5.9 Hz, 2H), 7.16 (t, J=8.9, 8.8 Hz, 2H), 6.31
(q, J=5.1 Hz, 1H), 4.49–4.36 (m, 2H), 4.00 (q, J=7.2 Hz, 2H), 3.49
(s, 3H), 2.57 (s, 3H), 1.72 (d, J=3.5 Hz, 6H), 1.54 (d, J=4.8 Hz, 3H),
1.13 ppm (t, J=7.2 Hz, 3H); MS (ESI+): m/z 561.1 [M+H]+ (2%),
471.1 [MꢁC3H5O3]+ (88%), 445.1 [MꢁC5H10O3]+ (5%), 387.1 [ion un-
known] (5%).
1H), 7.80 (t, J=5.5 Hz, 1H), 7.38 (dd, J=8.6, 5.8 Hz, 2H), 7.06–7.00
(m, 2H), 6.45 (q, J=5.1 Hz, 1H), 4.59 (d, J=6.1 Hz, 2H), 4.20–4.16
(m, 2H), 3.62 (s, 2H), 3.61–3.49 (m, 3H), 3.35 (s, 3H), 2.62 (s, 3H),
1.76 (d, J=5.3 Hz, 3H), 1.09 ppm (s, 4H); MS (ESI+): m/z 591.6
[M+H]+.
1-((4-((4-Fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl-1,3,4-
oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyri-
midin-5-yl)oxy)-2-methylpropyl isopropyl carbonate (9): Using in-
itial method, 1a (1.05 g, 0.0063 mmol) and 1-chloro-2-methylpropyl
isopropyl carbonate (0.63 g, 0.0032 mmol) gave compound 9 as
1
a white solid (0.55 g, 42%); H NMR (400 MHz, CDCl3): d=8.21 (br
s, 1H), 7.74 (t, J=6.0 Hz, 1H), 7.35–7.38 (m, 2H), 7.02 (t, J=8.8 Hz,
2H), 6.44 (d, J=4.4 Hz, 1H), 4.71–4.74 (m, 1H), 4.57–4.60 (m, 2H),
3.64 (s, 3H), 2.63 (s, 3H), 2.28–2.31 (m, 1H), 1.82 (s, 3H), 1.81 (s,
3H), 1.24 (d, J=4.0 Hz, 3H), 1.16 (d, J=6.0 Hz, 3H), 1.03–1.07 ppm
(m, 6H); MS (ESI+): m/z 603.3 [M+H]+.
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[12] J. K. Rockstroh, E. DeJesus, J. L. Lennox, J. Acquired Immune Defic. Syndr.
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EtOAc (150 mL). The organic solution was washed successively
with water (100 mL), and brine (100 mL). The organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was subjected to flash chromatography on silica gel
(EtOAc/hexane, 9:1) to afford the desired product as a white solid
(28.8 g, 85%); 1H NMR (500 MHz, CDCl3): d=8.16 (s, 1H), 7.89 (t,
J=6 Hz, 1H), 7.38 (dd, J=8 Hz, J=5.6 Hz, 2H), 7.02 (t, J=8 Hz,
2H), 5.92 (s, 2H), 4.57 (d, J=6.0 Hz, 2H), 3.65 (s, 3H), 2.65 (s, 3H),
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The authors wish to thank Ray McClain for purification support,
Chris Culberson for computational chemistry support, and James
Small for structural analysis support (NMR). Cuyue Tang and
Thomas Skopek are acknowledged for their contributions to the
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and final compounds.
Keywords: antiviral agents · colonic absorption · controlled-
release formulation · HIV-1 · once-daily dosing · prodrugs ·
raltegravir
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Received: September 11, 2014
Published online on && &&, 0000
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FULL PAPERS
A. M. Walji,* R. I. Sanchez, S.-D. Clas,
R. Nofsinger, M. de Lera Ruiz, J. Li,
A. Bennet, C. John, D. J. Bennett,
J. M. Sanders, C. N. Di Marco, S. H. Kim,
J. Balsells, S. S. Ceglia, Q. Dang,
K. Manser, B. Nissley, J. S. Wai, M. Hafey,
J. Wang, G. Chessen, A. Templeton,
J. Higgins, R. Smith, Y. Wu, J. Grobler,
P. J. Coleman
From twice to once daily: In an effort
to identify once-daily HIV therapeutics,
prodrugs of the HIV integrase inhibitor
raltegravir were designed to have en-
hanced colonic absorption leading to
the discovery of MK-8970 as a potential
candidate for further development.
&& – &&
Discovery of MK-8970: An Acetal
Carbonate Prodrug of Raltegravir with
Enhanced Colonic Absorption
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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