Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu 5 PAM

Article abstract of DOI:10.1016/j.bmcl.2012.04.112

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu₃) NAM probe (ML289) with 15-fold selectivity versus mGlu₂. The mGlu₃ NAM was discovered via a 'molecular switch' from a closely related, potent mGlu₅ positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC ₅₀ value of 0.66 μM and is inactive against mGlu₅.

Full text of DOI:10.1016/j.bmcl.2012.04.112

Bioorganic & Medicinal Chemistry Letters 22 (2012) 3921–3925
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3
(mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM
Douglas J. Sheffler a,b,c, , Cody J. Wenthur a,b, , Joshua A. Bruner b, , Sheridan J.S. Carrington a,b
Paige N. Vinson a,b, Kiran K. Gogi a,b, Anna L. Blobaum a,b,c, Ryan D. Morrison a,b,c, Mitchell Vamos e,
Nicholas D.P. Cosford e, Shaun R. Stauffer a,b,d, J. Scott Daniels a,b,c, Colleen M. Niswender a,b
,
,
P. Jeffrey Conn a,b,c, Craig W. Lindsley a,b,c,d,
⇑
a Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
b Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, Nashville, TN 37232, USA
c Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA
d Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA
e Apoptosis and Cell Death Research Program and Conrad Prebys Center for Chemical Genomics, Sanford-Burnham Medical Research Institute,
10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu3) NAM
probe (ML289) with 15-fold selectivity versus mGlu2. The mGlu3 NAM was discovered via a ‘molecular
switch’ from a closely related, potent mGlu5 positive allosteric modulator (PAM), VU0092273. This
Received 2 April 2012
Revised 19 April 2012
Accepted 23 April 2012
Available online 30 April 2012
NAM (VU0463597, ML289) displays an IC50 value of 0.66
lM and is inactive against mGlu5.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Metabotropic glutamate receptor 3
mGlu3
Molecular switch
NAM
The metabotropic glutamate receptors (mGlus) are members of
the GPCR family C, characterized by a large extracellular amino-ter-
minal agonist (venus fly-trap) binding domain.1,2 Eight mGlus have
been cloned, sequenced, and assigned to three groups (Group I:
mGlu1 and mGlu5; Group II: mGlu2 and mGlu3; Group III:
mGlu4,6,7,8) based on their sequence homology, pharmacology,
and coupling to effector mechanisms.1,2 Highly subtype-selective
allosteric ligands (both PAMs, positive allosteric modulators, and/
or NAMs, negative allosteric modulators) have been developed for
mGlu1, mGlu2, mGlu4, mGlu5, and mGlu7.3–11 However, aside from
mGlu2 PAMs, most Group II ligands do not discriminate between
mGlu2 and mGlu3; a necessary requirement as these two receptors
have highly divergent expression and function.12–15 Thus, due to a
lack of selective small molecule probes, it has been difficult to dis-
cern distinct pharmacological roles for mGlu3, though numerous
studies suggest mGlu3 is involved in glial-neuronal communication
and may have therapeutic potential for the treatment of schizo-
phrenia, Alzheimer’s disease, and depression.3–5,12,16–18
To date, only two mGlu3 NAMs have been reported (Fig. 1).19,20
The first, reported by Addex, is RO4491533 (1), a dual mGlu2/
mGlu3 NAM (mGlu2 IC50 = 296 nM, mGlu3 IC50 = 270 nM) based
on a benzodiazepinone nucleus that was efficacious in preclinical
cognition and depression models.19 At about the same time, Lilly
disclosed LY2389575 (2) as a selective mGlu3 NAM;20 however,
when measuring native coupling of these receptors to G protein-
coupled inwardly-rectifying potassium (GIRK) channels via
⇑
Corresponding author.
E-mail address: craig.lindsley@vanderbilt.edu (C.W. Lindsley).
Figure 1. Structures of mGlu3 NAMs RO4491533 (1) and LY2389575 (2), both dual
These authors contributed equally to this work.
mGlu2/mGlu3 NAMs.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.04.112

3922
D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3921–3925
thallium flux,21 we have observed that 2 is only ꢀ4-fold selective
Alternate Aryl, Heteroaryl
O
for mGlu3 over mGlu2 (mGlu2 IC50 = 17 lM, mGlu3 IC50 = 4.2 l
M).22
Alkyl, Cycloalkyl
N
Thus, there is a critical need for potent and selective mGlu3 ligands.
In the absence of an HTS campaign to identify novel mGlu3
NAMs, we elected to take advantage of the propensity of certain
mGlu5 PAM chemotypes to easily modulate the mode of pharma-
cology or mGlu subtype selectivity with subtle structural altera-
tions, that is ‘molecular switches’.23–27 One such chemotype that
we26,27 and others28 have reported on with a high propensity for
displaying ‘molecular switches’ is represented by VU0092273 (3),
a potent MPEP-site mGlu5 PAM (Fig. 2).27 Compound 3 also pos-
OH
Alternate Amide Moieties
3
, VU0092273
Figure 3. Library optimization strategy for VU0092273 (3) to improve mGlu3 NAM
activity while simultaneously eliminating mGlu5 PAM activity.
sessed weak mGlu3 NAM activity (IC50 ꢀ10
lM, inhibits EC80 by
72%, Fig. 2B), but otherwise showed no activity at the six other
O
O
O
N
OH
a
N
b
mGlu subtypes.
Thus, 3 became our lead compound from which to develop a po-
tent and selective mGlu3 NAM. As we have previously reported,
due to the steep nature of allosteric modulator SAR (especially in
series prone to ‘molecular switches’), we pursued an iterative par-
allel synthesis approach for the chemical optimization of 3.3,4 Pre-
vious work in this scaffold indicated that mGlu5 PAM activity could
be greatly diminished with substitution other than fluorine on the
distal aryl ring, as well as with modifications to the amide moi-
ety.26 Therefore, our first generation library design (Fig. 3) initially
held the 4-hydroxypiperidine amide constant, while surveying a
diverse array of functionalized aryl/heteroaryl rings as well as
other aliphatic groups. Once mGlu3-preferring modifications were
identified, these would be maintained while an amide scan would
be performed to improve mGlu3 NAM activity while eliminating
mGlu5 PAM activity.
Our first 48-member library was prepared as shown in Scheme
1, and purified, to >98% purity, by reverse phase chromatography.29
Commercial 4-iodobenzoic acid 4 was coupled to 4-hydroxypiper-
dine, under standard EDC/HOBt conditions, to provide amide 5 in
95% yield. Once synthesized, 5 then underwent Sonogashira cou-
pling reactions with a diverse array of 48 functionalized terminal
acetylenes to provide analogs 6.30 True to allosteric modulator
SAR, 47/48 of the analogs were either inactive on mGlu3 (IC50
I
OH
O
I
OH
4
5
6
R
N
OH
7, VU0457299
mGlu3 IC50 = 3.8 µM
%Glu Min = 10.4
MeO
Scheme 1. Reagents and conditions: (a) EDC, DMAP, DCM, DIPEA, 95%; (b) 20% CuI,
5% Pd(PPh3)4, 48 acetylenes (1.1 equiv), DMF, DIEA, 60 °C, 1 h, 15–90%.
Interestingly, the regioisomeric 2-OMe and 3-OMe congeners were
inactive.
Based on these data, the next round of library synthesis held the
4-methoxyphenyl moiety in 7 constant, and 48 amines31 were em-
ployed to survey alternative amides. This library, prepared accord-
ing to Scheme 2, was far more productive, providing several
analogs 10 with mGlu3 NAM potencies below 10 lM; however,
SAR was still quite steep (Table 1). In general, polar (10a–e) and ba-
sic substituents (10f and 10g) were the most efficacious. Of great
interest was the enantioselective mGlu3 inhibition displayed by
the (S)-piperidine carboxylic acid 10c (IC50 = 5.7
enantiomer 10d (IC50 >>10 M, essentially inactive). This result
led us to resolve racemic 3-hydroxymethyl analog 10e
>10 lM) or only afforded modest inhibition (5–50% Glu Min) of
the glutamate EC80. Only one compound, 7 (VU0457299), possess-
ing a 4-methoxyphenyl moiety, displayed mGlu3 NAM potency be-
lM) and the (R)-
l
low 10
lM
(mGlu3 IC50 = 3.8
l
M,
%
Glu Min = 10.4 2.1).
Figure 2. (A) Structure of VU0092273 (3), a potent mGlu5 PAM (pEC50 = 6.57 0.09, EC50 = 0.27
lM). (B) mGlu5 PAM concentration–response curve (CRC) in presence of an
EC20 of glutamate. (C) mGlu3 antagonist CRC 3 displayed weak NAM activity at mGlu3 (IC50 >10
lM, inhibits EC80 ꢀ72%).

D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3921–3925
3923
O
O
We next evaluated the selectivity of 11(VU0463597) between
mGlu2 and mGlu5. Utilizing our mGlu2 GIRK line, the IC50 was
OH
NR1R2
O
much greater than 10
the highest concentration tested (30
l
M, with the CRC not reaching baseline at
OMe
lM) (Fig. 5A, triangles). Simi-
b
a
I
larly, 11 was inactive for potentiating an EC20 concentration of glu-
tamate (Fig. 5B, triangles) or inhibiting an EC80 concentration of
glutamate (Fig. 5C, triangles) in our standard mGlu5 calcium assay.
As our calcium assays typically drive our mGlu drug discovery pro-
grams, we also evaluated 11 (VU0463597) in an mGlu3 calcium as-
say in which mGlu3 is co-expressed with the promiscuous G
p-OMePh
p-OMePh
8
9
10
Scheme 2. Reagents and conditions: (a) (i) 20% CuI, 5% Pd(PPh3)4, 4-OMePh
acetylene (1.1 equiv), DMF, DIEA, 60 °C, 1 h, 82%;(ii) KOH, aq MeOH, 95%; (b)
HNR1R2, EDC, DMAP, DCM, DIPEA, 40–96%.
protein G
(Fig. 5B and C, squares). Here, we see slightly im-
a
15
proved mGlu3 NAM potency (pIC50 = 6.18 0.03, IC50 = 0.66 lM, %
Table 1
Glu Min = 2.1 0.3) compared to the mGlu3/GIRK line. To verify
that 11 antagonizes mGlu3 via a non-competitive (allosteric)
mechanism of action, we next performed a Schild analysis. In these
Structures and activities of analogs 10
O
MeO
NR1R2
10
a
Compd
7
NR1R2
pIC50 SEM
5.42 0.04
5.30 0.06
IC50
3.8
5.0
(l
M)
%Glu Minb SEM
10.4 2.1
N
N
OH
OH
10a
4.4 0.7
OH
10b
10c
10d
5.61 0.07
5.24 0.01
2.5
5.7
>10
À1.1 0.5
2.2 1.1
N
N
N
CO2H
CO2H
OH
16.4 2.5
10e
10f
10g
5.69 0.04
2.1
0.5 0.4
7.6 3.2
9.6 2.1
N
N
>10
>10
N
N
a
Measured in an mGlu3 GIRK assay.
% Glu Min is the % inhibition of the compound on an EC80 concentration of
b
glutamate. Values represent the mean standard error mean for three independent
experiments performed in triplicate.
(IC50 = 2.1 lM), which afforded a full block of the EC80. Following
Scheme 2, both the (R)- and (S)-enantiomers of 10e, 11
(VU0463597) and 12 (VU0463593) were prepared and assayed in
the mGlu3 GIRK assay (Fig. 4). Here, 11 (pIC50 = 5.83 0.05, IC50
1.5 M) was twofold more potent than 12 (pIC50 = 5.49 0.02,
IC50 = 3.3 M), but both afforded full blockade (% Glu Mins of
=
l
l
À4.4 1.9 and À1.7 1.3, respectively). Efforts now shifted to-
wards more fully characterizing 11 (VU0463597).
O
OH
O
OH
N
N
MeO
MeO
11, VU0463597
12, VU0463593
mGlu3 IC50 = 1.5 µM
% Glu Min = -4.4+1.9
mGlu2 IC50 >10 µM
mGlu3 IC50 = 3.3 µM
% Glu Min = -1.7+1.3
mGlu2 IC50 >10 µM
Figure 5. In vitro molecular pharmacology characterization of 11 (VU0463597). (A)
Concentration–response curves of mGlu2 and mGlu3 GIRK (antagonist mode). (B)
mGlu3 calcium (antagonist mode) and mGlu5 calcium (PAM mode). (C) mGlu3
calcium (antagonist mode) and mGlu5 calcium (antagonist mode).
Figure 4. Structures and activities of (R)-11 and (S)-12, mGlu3 NAMs.

3924
D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3921–3925
O
OH
O
OH
studies, 11 dose-dependently induced
a rightward shift and
decreased the maximal efficacy of the orthosteric agonist gluta-
mate (Fig. 6), consistent with a non-competitive (allosteric) mech-
anism of action. Thus, starting from a very potent mGlu5 PAM
N
N
CYPs
HO
(EC50 = 0.27 lM), we were able to optimize and develop a potent
MeO
11
13
and selective mGlu3 NAM with high selectivity (ꢀ15-fold) versus
O-dealkylation
mGlu2 and complete specificity versus mGlu5.
With this potent and selective mGlu3 NAM in hand, we began
profiling 11 in a battery of ancillary pharmacology and DMPK as-
says to assess the quality of this probe for potential in vivo stud-
ies. A Lead Profiling Screen at Ricerca32 (68 GPCRs, ion channels
Figure 7. Oxidative O-dealkylation of 11 in rat and human liver microsomes.
and transporters screened at 10
failed to identify any off target activities for 11 (no inhibi-
tion >25% at 10 M). In our tier 1 in vitro DMPK screen, com-
pound 11 displayed no P450 inhibition in human liver
microsomes (IC50 >30 M vs 3A4, 2C9, 2D6 and 1A2), high plasma
lM in radioligand binding assays)
may be required for in vivo efficacy with this first generation
mGlu3 NAM probe.
This project was an MLPCN Medicinal Chemistry FastTrack pro-
gram, and based on the profile of 11, it was declared an MLPCN
probe and assigned the identifier ML289.33 As such, ML289 is freely
available upon request.34
In summary, we have developed a potent, selective (>15-fold vs
mGlu2) and centrally penetrant mGlu3 NAM 11 (VU0463597 or
ML289) with a good overall CYP profile. ML289 is also highly selec-
l
l
protein binding with fraction unbound (fu) levels between 1% and
2% in both rat and and human plasma, respectively; fu deter-
mined in rat brain homogenate was 1%. Intrinsic clearance (CLint
)
determined in rat and human liver microsomes indicated that
compound 11 was rapidly cleared in vitro (rat, CLint = 240 mL/
min/kg; human, CLint = 571.8 mL/min/kg). An in vitro to in vivo
clearance correlation was established, as compound 11 was found
to be a moderately cleared compound in rat (CL = 33 mL/min/kg)
following intravenous administration (1 mg/kg); the low volume
of distribution at steady state (Vss 0.6 L/kg) and moderate clear-
ance produced a relatively short t1/2 (16.8 min) in vivo. Metabo-
lite ID studies in rat and human liver microsomes (Fig. 7)
indicated that the principle biotransformation pathway was
P450-mediated O-demethylation of 11 to generate the phenol
13, a metabolite that was subsequently shown to be inactive at
mGlu3 and mGlu5.
tive versus mGlu5, which is notable as our lead was a 0.27 lM
mGlu5 PAM, and suggests ligand cross-talk between allosteric
binding sites on mGlu3 and mGlu5. Once again, a subtle ‘molecular
switch’, in the form of a p-OMe moiety, conferred selective mGlu3
inhibition over mGlu5 potentiation. Further chemical optimization
efforts, as well as detailed molecular pharmacological character-
ization of ML289, are in progress and will be reported in due
course.
Acknowledgments
This work was supported by grants from the NIH. Vanderbilt is a
Specialized Chemistry Center within the Molecular Libraries Probe
Centers Network (U54 MH84659).
As our earlier SAR work indicated that the methyl ether was
critical for mGlu3 NAM activity, we performed an IP plasma:brain
level (PBL) study to determine if we could achieve meaningful
CNS exposure if first-pass metabolism was bypassed. Signifi-
cantly, in a 10 mg/kg (10% Tween80 in 0.5% methylcellulose) IP
References and notes
plasma/brain level (PBL) study, we observed a brain (16.3
lM)/
plasma (9.7 M) ratio of 1.67, indicating that 11 (VU0463597)
was indeed centrally penetrant. Based on brain homogenate bind-
l
1. Schoepp, D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1431.
2. Conn, P. J.; Pin, J.-P. Annu. Rev. Pharmacol. Toxicol. 1997, 37, 205.
3. Melancon, B. J.; Hopkins, C. R.; Wood, M. R.; Emmitte, K. A.; Niswender, C. M.;
Christopoulos, A.; Conn, P. J.; Lindsley, C. W. J. Med. Chem. 2012, 55, 1445.
4. Conn, P. J.; Christopolous, A.; Lindsley, C. W. Nat. Rev. Drug Disc. 2009, 8, 41.
5. Conn, P. J.; Lindsley, C. W.; Jones, C. Trends Pharmacol. Sci. 2009, 30, 25.
6. Robichaud, A. J.; Engers, D. W.; Lindsley, C. W.; Hopkins, C. R. ACS Chem.
Neurosci. 2011, 2, 433.
ing studies, this correlates to ꢀ163 nM free in rat brain at the
10 mg/kg dose, a value below the mGlu3 IC50 (0.66 lM); thus, in
order to provide adequate target engagement, a 50 mg/kg dose
7. Sheffler, D. J.; Pinkerton, A. B.; Dahl, R.; Markou, A.; Cosford, N. D. P. ACS Chem.
Neurosci. 2011, 2, 382.
8. Owen, D. R. ACS Chem. Neurosci. 2011, 2, 394.
9. Emmitte, K. A. ACS Chem. Neurosci. 2011, 2, 443.
10. Stauffer, S. R. ACS Chem. Neurosci. 2011, 2, 450.
11. Suzuki, G.; Tsukamoto, N.; Fushiki, H.; Kawagishi, A.; Nakamura, M.;
Kurihara, H.; Mitsuya, M.; Ohkubo, M.; Ohta, H. J. Pharmacol. Exp. Ther. 2007,
323, 147.
12. Harrision, P. J.; Lyon, L.; Sartorius, L. J.; Burnet, P. W. J.; Lane, T. A. J.
Psychopharmacol. 2008, 22, 308.
13. Kew, J. N. C.; Kemp, J. A. Psychopharmacology 2005, 179, 4.
14. Woltering, T. J.; Wichmann, J.; Goetschi, E.; Knoflach, F.; Ballard, T. M.;
Huwyler, J.; Gatti, S. Bioorg. Med. Chem. Lett. 2010, 20, 6969.
15. Corti, C.; Battaglia, G.; Molinaro, G.; Riozzi, B.; Pittaluga, A.; Corsi, M.;
Mugnaini, M.; Nicoletti, F.; Bruno, V. J. Neurosci. 2007, 27, 8297.
16. Moghaddam, B.; Adams, B. W. Science 1998, 281, 1349.
17. Matrrisciano, F.; Panaccione, I.; Zusso, M.; Giusti, P.; Tatarelli, R.; Iacovelli, L.;
Mathe, A. A.; Gruber, S. H.; Nicoletti, F.; Girardi, P. Mol. Psychiarty 2007, 12, 704.
18. Markou, A. Biol. Psychiatry 2007, 61, 17.
19. Campo, B.; Kalinichev, M.; Lambeng, N.; El Yacoubi, M.; Royer-Urios, I.;
Schneider, M.; Legarnd, C.; Parron, D.; Girard, F.; Bessif, A.; Poli, S.; Vaugeois, J.-
M.; Le Poul, E.; Celanire, S. J. Neurogenet. 2011, 24, 152.
20. Caraci, F.; Molinaro, G.; Battaglia, G.; Giuffrida, M. L.; Riozzi, B.; Traficante, A.;
Bruno, V.; Cannella, M.; Mero, S.; Wang, X.; Heinz, B. A.; Nisenbaum, E. S.;
Figure 6. Schild analysis of 11 (VU0463597). The concentration–response of
glutamate for mGlu3 GIRK is non-competitively inhibited by 11.

D. J. Sheffler et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3921–3925
Britton, T. C.; Drago, F.; Sortino, M. A.; Copani, A.; Nicoletti, F. Mol. Pharm. 2011, 30. Representative acetylenes employed in the 48-member library:
3925
79, 618.
R = H, 4-Me, 4-Et, 2-OMe, 3-OMe, 4-OMe, 4-CF3, 4-NMe2,
2-Napthyl, 2,6-di-CF3, 4-Cl, 2-Cl, 3-Cl, 4-F, 2-F, 3-F, 4-tBu
21. Niswender, C. M.; Johnson, K. A.; Luo, Q.; Ayala, J. E.; Kim, C.; Conn, P. J.;
Weaver, C. D. Mol. Pharm. 2008, 73, 1213.
22. CRCs for LY2389575 (2) in our GIRK assays:
R
N
OBn
O
N
OH
Me2N
S
O
31. Representative amines employed in the 48-member library:
H
H
H
H
N
N
N
N
NH2
NH2
OH
O
OH
N
H
23. Sharma, S.; Rodriguez, A.; Conn, P. J.; Lindsley, C. W. Bioorg. Med. Chem. Lett.
2008, 18, 4098.
24. Sharma, S.; Kedrowski, J.; Rook, J. M.; Smith, J. M.; Jones, C. K.; Rodriguez, A. L.;
Conn, P. J.; Lindsley, C. W. J. Med. Chem. 2010, 52, 4103.
H
N
NH
NH2
HO
NH2
NH2
HO
25. Wood, M. R.; Hopkins, C. R.; Brogan, J. T.; Conn, P. J.; Lindsley, C. W.
Biochemistry 2011, 50, 2403.
26. Williams, R.; Manka, J. T.; Rodriguez, A. L.; Vinson, P. N.; Niswender, C. M.;
Weaver, C. D.; Jones, C. K.; Conn, P. J.; Lindsley, C. W.; Stauffer, S. R. Bioorg. Med.
Chem. Lett. 2011, 21, 1350.
27. Rodriguez, A. L.; Grier, M. D.; Jones, C. K.; Herman, E. J.; Kane, A. S.; Smith, R. L.;
Williams, R.; Zhou, Y.; Marlo, J. E.; Days, E. L.; Blatt, T. N.; Jadhav, S.; Menon, U.;
Vinson, P. N.; Rook, J. M.; Stauffer, S. R.; Niswender, C. M.; Lindsley, C. W.;
Weaver, C. D.; Conn, P. J. Mol. Pharm. 2010, 78, 1105.
28. Ritzen, A.; Sindet, R.; Hentzer, M.; Svendsen, N.; Brodbeck, R. M.; Bungaard, C.
Bioorg. Med. Chem. Lett. 2009, 19, 3275.
OH
H
N
NH
R
NH
H2N
H2N
N
N
HO
Ar (Het)
32. For full information on the targets in the Lead Profiling Screen at Ricerca, please
see: www.ricerca.com.
33. For information on the MLPCN please see: http://mli.nih.gov/mli/mlpcn/.
34. To
request
your
free
sample
of
ML289,
please
email:
29. Leister, W. H.; Strauss, K. A.; Wisnoski, D. D.; Zhao, Z.; Lindsley, C. W. J. Comb.
Chem. 2003, 5, 322.
craig.lindsley@vanderbilt.edu.