Design and synthesis of sarolaner, a novel, once-a-month, oral isoxazoline for the control of fleas and ticks on dogs

Article abstract of DOI:10.1016/j.bmcl.2016.02.027

Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal health companies in their search for novel pesticides and ectoparasiticides. Herein we report the discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral treatment of flea and tick infestation on dogs.

Full text of DOI:10.1016/j.bmcl.2016.02.027

Bioorganic & Medicinal Chemistry Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of sarolaner, a novel, once-a-month, oral
isoxazoline for the control of fleas and ticks on dogs
Michael P. Curtis a, Valerie Vaillancourt a, Richard M. Goodwin a, Nathan A. L. Chubb a, William Howson a,
Tom L. McTier b, Aleah Pullins b, Erich W. Zinser b, Patrick F. M. Meeus b, Debra J. Woods b, Laura Hedges c,
Tim Stuk d, Jeffrey E. Price d, Jason D. Koch d, Sanjay R. Menon a,
⇑
a Department of Medicinal Chemistry, Zoetis Inc., Veterinary Medicine Research and Development, 333 Portage St., Kalamazoo, MI 49007, USA
b Department of Parasitology, Zoetis Inc., Veterinary Medicine Research and Development, 333 Portage St., Kalamazoo, MI 49007, USA
c Department of Metabolism & Safety, Zoetis Inc., Veterinary Medicine Research and Development, 333 Portage St., Kalamazoo, MI 49007, USA
d Department of Pharmaceutical Sciences, Zoetis Inc., Veterinary Medicine Research and Development, 333 Portage St., Kalamazoo, MI 49007, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Over the last decade, the isoxazoline motif has become the intense focus of crop protection and animal
health companies in their search for novel pesticides and ectoparasiticides. Herein we report the
discovery of sarolaner, a proprietary, optimized-for-animal health use isoxazoline, for once-a-month oral
treatment of flea and tick infestation on dogs.
Received 13 January 2016
Revised 9 February 2016
Accepted 10 February 2016
Available online xxxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Sarolaner
Isoxazoline
Ectoparasiticide
Oral flea and tick agent
F
F
F
F
F
F
The companion animal parasiticide market represents a major
and rapidly growing segment in the animal health-industry, with
an estimated value of approximately US $4.3 billion in 2013
(Source: Vetnosis). Ectoparasiticides, which control flea, tick, lice
and mite infestations, are important to pet owners since they not
only protect their pets against the direct impact of these parasites,
but also may help to prevent the transmission of diseases by these
parasites (e.g., lyme disease).1 The introduction of fipronil in 1994
generated a significant paradigm shift among ectoparasiticides,
providing for the first time a highly effective and convenient topical
monthly control method.2 Significant market success resulted with
annual global sales of FrontlineÒ (Merial) and other animal health
fipronil products reaching over US $800 million in 2012.3 Conse-
quently, over the last two decades, many animal health companies
have dedicated significant efforts toward the development of novel
and differentiated products, in specific, once-a-month, orally
administered flea and tick agents for companion animals.4 Much
of this work has been based on leveraging the discovery efforts
for new pesticides conducted by agrochemical companies. At the
time that we embarked on our own active research in this arena,
there were multiple reports in the patent literature of isoxazolines
F
O
F
F
O
O
N
N
N
Cl
F3C
Cl
Cl
Cl
Cl
F
H
N
H
N
O
O
O
N
O
O
SO2Me
N
H
N
H
CF3
CF3
O
Afoxolaner
Fluralaner
Sarolaner
Figure 1. Ectoparasiticidal isoxazolies.
exhibiting insecticidal activity from such sources and representa-
tive examples of this class have recently entered the market for
animal health use (Fig. 1).5 Herein we report the discovery of
sarolaner, a once-a-month, oral isoxazoline specifically optimized
for the treatment of flea and tick infestation on dogs.
Our initial work in the area of isoxazolines culminated in the
discovery of the novel isoxazoline azetidines with oral flea and tick
activity in dogs.6 The in vitro ectoparasiticidal data and oral dog
pharmacokinetic (PK) profiles of two representative examples, 1
and 2, synthesized in the course of that effort, are presented in
Table 1.7,8 With the understanding that plasma is the efficacious
compartment, or at least an excellent surrogate for the efficacious
compartment, an inspection of these data reveals that while 1
⇑
Corresponding author. Tel.: +1 269 359 9366.
E-mail address: sanjay.menon@zoetis.com (S.R. Menon).
http://dx.doi.org/10.1016/j.bmcl.2016.02.027
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Curtis, M. P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.027

2
M. P. Curtis et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
Table 1
In vitro ectoparasiticidal activities and oral dog PK profiles for representative isoxazoline azetidines 1 and 2
Compound
Flea feeda
Soft Tick feeda
ED50 LD100
g/mL) g/mL)
Computed propertiesb
LD80
M.W.
AlogP
PSA
(lg/mL)
(
l
(l
F
F
1
2
1
10
0.03
0.03
534
532
6.3
5.3
42
62
N.D.c
N.D.c
F
O
N
Cl
Cl
Cl
X
N
O
1, X = F
2, X = OH
a
b
c
Ref. 7.
Pipeline pilot.
Compounds inactive or weakly active in the flea feed assay were not progressed into the soft tick feed assay.
Previous reports in the patent literature demonstrated the
superior ability of an ortho substitution in the linker aryl ring of
an isoxazoline to improve insecticidal potency. Thus, the place-
ment of a cyano substituent ortho to the triazole ring (Fig. 2) was
shown to drastically improve insecticidal potency.10 From this,
we postulated that we could enhance the in vitro potency of 2,
while maintaining its favorable PK profile, by placing a cyano sub-
stituent ortho to the azetidine attachment on the linker phenyl as
shown in the generic structure 3.
F
F
F
F
F
F
F
O
F
F
O
O
N
N
N
"Head" Ar
Ar
Cl
increased potency
CN
N
X
"Linker"
Cl
OH
NC
N
N
N
N
O
"Tail"
3
R
N
N
X = H, halogen
R = alkyl, cycloalkyl, etc.
Attempted synthesis of a representative analog of the generic
structure 3 started with the bromoiodo arene intermediate 4
(Scheme 1).11 In situ Grignard generation, followed by the addition
of the azetidinone building block led to hydroxyazetidine 5. Some-
what unexpectedly, cyanation of 5, in place of affording the
intended cyano substituted hydroxyazetidine 3, led to the cyclized
lactone 6, presumably arising from facile intramolecular attack of
the hydroxyl on the cyano functional group and hydrolysis of the
intermediate oxoamidine.
Figure 2. Hypothesized potency optimization of 2 through placement of a CN
group.
exhibits superior in vitro flea and tick potency, 2 affords a superior
dog PK profile due to its higher systemic plasma concentrations.9
The challenge in front of us was to incorporate both of these features
in a single molecule; thus, we intended to modulate the structure of
2 to improve in vitro potency (flea feed LD80 <1
lg/mL; soft tick feed
Opportunistic synthesis and in vitro testing of amide 7 revealed
it to possess promising insecticidal potency (cf. 2); even more
ED50 <0.1 g/mL) while maintaining its dog PK profile.
l
F
F
F
O
F
F
N
F
O
N
Cl
b, c
a
Cl
Cl
Cl
OH
Br
Cl
Cl
N
Br
I
Ph
4
5
Ph
F
F
F
F
F
F
O
O
N
N
d, e
Cl
Cl
Cl
Cl
Cl
Cl
Ph
Ph
O
N
N
O
O
O
O
6
7
Scheme 1. Reagents and conditions: (a) iPrMgCl, THF, azetidinone, ꢀ40 °C to ꢀ10 °C, 52%; (b) Zn(CN)2, Pd(PPh3)4, DMF, microwave, 150 °C; (c) H2O, 70 °C, 58% (steps b–c);
(d) chloroethyl chloroformate, DCM-acetonitrile, MeOH, reflux, 71%; (e) c-PrCOCl, TEA, DCM, 46%.
Please cite this article in press as: Curtis, M. P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.027

M. P. Curtis et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
3
Table 2
In vitro ectoparasiticidal activities and oral dog PK profiles for spirolactone 7 and spiroether 11
Compound
Flea feeda
Soft tick feeda
ED50 LD100
g/mL) g/mL)
Computed propertiesb
LD80
M.W.
AlogP
PSA
(
lg/mL)
(l
(l
F
F
7
11
1
0.3
0.03
0.01
0.1
0.03
558
528
5.5
5.0
68
51
F
O
N
Cl
X
Cl
O
N
)
O
(
n
O
7, X = Cl, n = 1
11, X = F, n = 0
a
Ref. 7.
Pipeline pilot.
b
F
F
F
F
F
O
N
F
O
N
a
b, c
Cl
Cl
F
Cl
OH
F
Br
Cl
Ph
Ph
N
N
O
O
Ph
8
9
Ph
F
F
F
F
F
O
F
O
N
N
d, e, f
Cl
Cl
F
Cl
O
F
Cl
Ph
Ph
N
N
O
O
10
11
Scheme 2. Reagents and conditions: (a) Pd(OAc)2, Xantphos, MeOH, CO (1 atm), 70%; (b) LiBH4, THF, 95%; (c) MsCl, DCM, 0 °C to 35 °C, 80%; (d) chloroethyl chloroformate,
DCM, acetonitrile, reflux; (e) MeOH, reflux, 85% (steps d–e); (f) c-PrCOCl, TEA, DCM, 95%.
interestingly, evaluation of 7 in a dog PK study showed it to exhibit
a reasonable enough PK profile (factoring in the potential liability
of the lactone functionality) following oral administration (Table 2)
that rendered it worthy of further exploration.
We next investigated the effect of modification of the lactone
ring to improve both activity and pharmacokinetic parameters.
Gratifyingly, reduction of the lactone to the cyclic ether, con-
comitant with optimization of the head aryl ring (Cl to F substi-
tution),12 afforded 11 (Scheme 2), exhibiting improved flea and
tick activities in vitro as well as a more desirable oral dog PK
profile (Table 2).
Lead compound 11 presented an exciting advance on the path
to meeting our initial laboratory objectives vis-à-vis 1 and 2. In
an attempt to further optimize the PK properties of 11, while main-
taining or even improving in vitro potency, a focused set of amide
tail replacements with a range of physicochemical properties (lipo-
philic to polar) was investigated.13 From this investigation, 13,
bearing a polar SO2Me substitution on the amide tail (Scheme 3)
was identified as exhibiting the optimal balance of in vitro potency,
dog PK and physicochemical properties to potentially target a
once-a-month oral ectoparasiticidal profile (Table 3). Since
previous reports on antiparasitic isoxazolines had demonstrated
superior activity for the (S)-enantiomer, racemic 13 was further
separated and tested as its (R)- and (S)-enantiomers; the in vitro
activity and dog oral PK profile for the active (S)-enantiomer
((S)-13; sarolaner) are included in Table 3.14,15
(S)-13 (sarolaner) was subsequently progressed into a dog effi-
cacy study wherein, at 2.5 mg/kg oral dose, it exhibited P99.9%
efficacy for fleas (Ctenocephalides felis) and 100% for ticks (Rhipi-
cephalus sanguineus) for the entire duration of the 28 day study
period (Table 4).16 Based on its promising PK profile (Table 5), effi-
cacy profile and additional in vitro and in vivo biological profiling,
(S)-13 (sarolaner) was progressed into development; details of
these studies will be reported separately.
In summary, this communication outlines the discovery of sar-
olaner, a proprietary, optimized-for-animal health use isoxazoline
for once-a-month, oral treatment of flea and tick infestation on
dogs, starting from an azetidine based isoxazoline lead series.
Please cite this article in press as: Curtis, M. P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.027

4
M. P. Curtis et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
F
F
F
F
F
F
F
F
F
O
O
O
N
N
N
Cl
Cl
Cl
b
c
F
F
F
Cl
Cl
Cl
O
O
N
N
NH
O
O
O
SO2Me
SO2Me
N
N
O
12
13
(R)-13
(S)-13 (Sarolaner)
MeO2S
O
a
OH
MeO2S
Scheme 3. Reagents and conditions: (a) CDI, DMF; (b) MTBE, 90%; (c) chiral separation.
Table 3
In vitro ectoparasiticidal activities and oral dog PK profile for sarolaner (S)-13
Compound
Flea
Soft tick feeda
Computed propertiesb
feeda
LD80
ED50
LD100
g/mL)
M.W. AlogP PSA
(
lg/mL)
(lg/mL) (l
F
F
rac-13
(R)-13
(S)-13 (Sarolaner) 0.3
1
3
0.03
>0.1
0.003
0.03
>0.1
0.003
580
3.7
94
F
O
N
Cl
F
Cl
O
N
O
SO2Me
13
a
Ref. 7.
Pipeline pilot.
b
Table 4
Oral ectoparasiticidal efficacy of sarolaner in dogs
Count Day
Arithmetic mean flea
count (placebo control)
Arithmetic mean tick
count (placebo control)
Flea efficacy (C. felis) 2.5 mg/kg
sarolaner solution
Tick efficacy (R. sanguineus) 2.5 mg/kg
sarolaner solution
2
28
62.5
76.5
20.0
18.0
0.0a (100)
0.1a (99.8)
0.0a (100)
0.0a (100)
a
Mean counts are significantly different to control (P 6 0.05). Percent efficacy is given in brackets.
References and notes
Table 5
1. (a) Parola, P.; Davoust, B.; Raoult, D. Vet. Res. 2005, 36, 469; (b) Beugnet, F.;
Marie, J.-L. Vet. Parasitol. 2009, 163, 298; (c) Chomel, B. Vet. Parasitol. 2011, 179,
294; (d) Irwin, P. J. Trends Parasitol. 2014, 30, 104.
2. Hunter, J. S.; Keister, D. M.; Jeannin, P. Proceedings of the American Association
of Veterinary Parasitologists, 39th Annual Meeting, San Francisco, CA, 1994, p.
40.
3. http://en.sanofi.com/investors/key_facts_figures/net_sales/net_sales.aspx.
4. Woods, D. J.; Vaillancourt, V. A.; Wendt, J. A.; Meeus, P. F. Future Med. Chem.
2011, 3, 887.
5. (a) Shoop, W. L.; Hartline, E. J.; Gould, B. R.; Waddell, M. E.; McDowell, R. G.;
Kinney, J. B.; Lahm, G. P.; Long, J. K.; Xu, M.; Wagerle, T.; Jones, G. S.; Dietrich, R.
F.; Cordova, D.; Schroeder, M. E.; Rhoades, D. F.; Benner, E. A.; Confalone, P. N.
Vet. Parasitol. 2014, 201, 179; (b) Gassel, M.; Wolf, C.; Noack, S.; Williams, H.;
Ilg, T. Insect Biochem. Mol. Biol. 2014, 45, 111.
PK parameters of (S)-13 (sarolaner) in dogsa
Treatment
PK parameter
LS mean
IV
IV
IV
PO (fed)
PO (fed)
PO (fed)
CL (mL/min/kg)
Vdss (mL/kg)
t1/2 (h)
0.12b
2810b
289
297
919
Cmax (ng/mL)
Bioavailability (%F)
107
IV, intravenous; PO, per os (oral).
a
IV dose 2 mg/kg. PO dose 2.28–2.51 mg/kg. PO PK parameters, with the excep-
tion of t1/2, have been dose-normalized to 2 mg/kg. Dose normalized PO AUC0–1
was used to calculate %F.
6. Vaillancourt, V. A.; Chubb, N. A. L.; Curtis, M.; Howson, W.; Kyne, G. M.; Menon,
S.; Sheehan, S. M. K.; Skalitzky, D. J.; Wendt, J. A. U. S. Patent 8 415 310, 2013.
b
Arithmetic means reported in place of least-squares means.
Please cite this article in press as: Curtis, M. P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.027

M. P. Curtis et al. / Bioorg. Med. Chem. Lett. xxx (2016) xxx–xxx
5
7. The in vitro ectoparasiticidal activities for compounds 1, 2, 7, 11 and 13 were
determined as follows:
10. (a) Lahm, G. P.; Patel, K. M.; Pahutski, T. F.; Smith, B. K.; PCT Intl. Appl. WO 07/
075459, 2007.; (b) Lahm, G. P.; Cordova, D.; Barry, J. D.; Pahutski, T. F.; Smith, B.
K.; Long, J. K.; Benner, E. A.; Holyoke, C. W.; Joraski, K.; Xu, M.; Schroeder, M. E.;
Wagerle, T.; Mahaffey, M. J.; Smith, R. M.; Tong, M.-H. Bioorg. Med. Chem. Lett.
2013, 23, 3001.
Flea (Ctenocephalides felis) Membrane Feed Assay: compounds were dissolved
in DMSO and aliquots were added to citrated bovine blood in membrane
covered wells warmed to 37 °C. Adult fleas were newly emerged (3–7 days)
and unfed. Feeding chambers containing approximately 30 adult fleas were
placed onto the treated blood wells, and the fleas were allowed to feed on the
treated blood for 2 h. Fleas were observed for knockdown and/or death at 2 and
24 h. Each compound was tested at half-log intervals, and endpoint data was
11. Curtis, M.; Menon, S.; Vaillancourt, V. A.; Chubb, N. A. L.; Billen, D.; Greenwood,
S. D. W.; Stuk, T. L. U. S. Patent 8 466 115, 2013.
12. Aryl groups with varied combinations of halogen substitutions at the ortho,
meta and para positions were explored since such substitutions were observed
to impact in vitro potency. In the spirocyclic series, a Cl, F, Cl combination was
identified to be one of the optimal aryl group substitutions for in vitro potency.
13. (a) van de Waterbeemd, H.; Constantino, G.; Clementi, S.; Cruciani, G.; Valigi, R.
In van de Waterbeemd, H., Ed.; Methods and Principles in Medicinal
Chemistry; VCH: Weinheim, 1995; Vol. 2, pp 103–112; (b) Hajduk, P. J.;
Sauer, D. R. J. Med. Chem. 2008, 51, 553.
recorded as LD80 in lg/mL. LD80 is a subjective visual assessment of organism
viability, and is the lowest dose to cause P80% mortality.
Soft Tick (Ornithodorus turicata) Membrane Feed Assay: compounds were
dissolved in DMSO and aliquots were added to citrated bovine blood in
membrane covered wells warmed to 37 °C. Five nymphs (N3–N4) were placed
on the membrane, allowed to feed to repletion, and were placed in observation
chambers. Nymphs were observed for knockdown and/or death at 24 and 72 h.
Endpoint results for subjective visual assessment of organism viability were
recorded as ED50 (the lowest dose to cause P50% morbidity/mortality) and
14. (a) Ozoe, Y.; Asahi, M.; Ozoe, F.; Nakahira, K.; Mita, T. Biochem. Biophys. Res.
Commun. 2010, 391, 744
(b) Chiral separation was performed on
Chromatograph unit using the following set up: Column: OJ 30 mm
250 mm, 5 M; Mobile phase: A = CO2, B = 1:1 MeOH: DCM with 0.1% TEA;
a Berger Supercritical Fluid
LD100 (the lowest dose to cause 100% mortality) in
lg/mL.
x
8. All in vivo procedures were conducted according to state, national or
international regulations, and after appropriate ethical reviews. Subjects for
the pharmacokinetic studies were prepubertal to adult, purpose-bred beagles
(P6 months of age and 6–14 kg).
l
Gradient: isocratic, 23% B; Temperature: 40 °C; Flow rate: 100 mL/min; Outlet
pressure: 120 bar.
15. The synthesis of sarolaner is described in: Curtis, M.; Menon, S.; Vaillancourt,
V. A.; Chubb, N. A. L.; Billen, D.; Greenwood, S. D. W.; Stuk, T. L. U. S. Patent 8
466 115, 2013. The spectral data for sarolaner is as follows:
For the initial in vivo assessment of compounds 1, 2, 7, 11 and 13, three animals
were randomly allocated to each treatment group. For compounds 1, 2, 7 and
11, subjects were treated with the test materials (0.5 mg/kg) in a solution
formulation (1 mg/mL) of DMSO: 2-pyrrolidinone: Tetraglycol: Solutol HS15:
1H NMR (600 MHz, DMSO-d6) d: 7.82 (d, J = 6.24 Hz, 2H), 7.77 (d, J = 8.25 Hz,
1H), 7.70 (m, 2H), 5.13 (s, 2H), 4.58 (s, 2H), 4.37 (m, 2H), 4.26 (s, 2H), 4.23 (s,
2H), 3.16 (s, 3H); m/z (ESI) 579.0 [M-H]-.
Tween80 (5:15:50:28:2% v/v) via oral gavage, followed by
a water flush
(10 mL). Blood sampling commenced at 0.5 h post dose and continued for two
weeks post dose. For compound 13, subjects were treated with the test
16. Subjects for the efficacy study were adult, purpose-bred beagles (P 8 months
of age and 6 20 kg). Parasites used in the study were the cat flea (C. felis) and
the brown dog tick (R. sanguineus). Day 0 was the day dogs were treated with
test materials.
material (2.5 mg/kg) in
a solution formulation (20 mg/mL) of DMSO: 2-
pyrrolidinone: Tetraglycol: Solutol HS15: Tween80 (5:15:50:28:2% v/v) via
oral gavage, followed by a water flush (10 mL). Blood sampling commenced at
0.5 h post dose and continued for two months post dose. For the definitive PK
assessment of compound 13, as presented in Table 5, 12 animals (6 male, 6
female) were randomly allocated to two treatment groups. Subjects in
Treatment group 1 were treated with 13 via an intravenous bolus injection
(2 mg/kg) in a solution formulation (20 mg/mL) of DMSO: Glycerol Formal—
Solutol HS15 (2:1, w/w): Sterile water for injection (5:50:45% v/v). Subjects in
Treatment group 2 were each orally administered one 20 mg chewable tablet
Eight animals (four male and four female each) were randomly allocated to
each treatment group (placebo and sarolaner) based on Day -5 tick counts. All
subjects were treated via oral gavage (0.5 mL/kg) with either placebo (T01) or
sarolaner (T02; 2.5 mg/kg) in
a solution formulation of DMSO: 2-
pyrrolidinone: Tetraglycol: Solutol HS15: Tween80 (5:15:50:28:2% v/v) on
study Day 0. All dogs were infested with fleas and ticks prior to treatment and
approximately weekly thereafter for 5 weeks. Infestations were conducted by
applying 50 adult ticks (1:1 sex ratio) and 100 adult fleas gently to a site
proximal or adjacent to the shoulder blades and allowed to crawl into the
haircoat. Parasite counts, both flea and tick, were routinely conducted 24 hours
after flea infestation (48 hours after tick infestation) except on Day 2 where
both counts were conducted 48 hours post treatment with the test materials.
Dogs were examined for ticks beginning from the head and moving posteriorly
along the dorsal, lateral and ventral sides. Ticks were removed as they were
found and subsequently identified and assessed for viability. Dogs were
systematically combed for fleas using repeated strokes initially while standing,
starting from the head, then posteriorly along the dorsal, lateral and ventral
sides. Combing was continued until no fleas were recovered for about 5
minutes. Each animal was examined for a minimum of 10 minutes.
of 13. Administration of the oral dose was followed by
a water flush
(approximately 15 mL). Blood sampling commenced at 2 min post dose, and
continued for two months post dose. Blood was held on wet ice prior to
centrifugation and removal of plasma. Plasma was stored at 610 °C until
analysis by protein precipitation and ultra performance liquid chromatography
with tandem mass spectrometry.
9. An understanding of the PKPD for systemically active ectoparasiticides has
been derived from extensive observations from internal discovery
programmes, but also see: (a) Kunkle, B. N.; Drag, M. D.; Chester, T. S.;
Larsen, D. L. Vet. Parasitol. 2014, 201, 204; (b) Meinke, P. T.; Colletti, S. L.; Fisher,
M. H.; Wyvratt, M. J.; Shih, T. L.; Ayer, M. B.; Li, C.; Lim, J.; Ok, D.; Salva, S.;
Warmke, L. M.; Zakson, M.; Michael, B. F.; deMontigny, P.; Ostlind, D. A.; Fink,
D.; Drag, M.; Schmatz, D. M.; Shoop, W. L. J. Med. Chem. 2009, 52, 3505.
Please cite this article in press as: Curtis, M. P.; et al. Bioorg. Med. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.bmcl.2016.02.027