N-{3-[2-(4-alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy derivatives as acetyl-CoA carboxylase inhibitors - Improvement of cardiovascular and neurological liabilities via structural modifications

Article abstract of DOI:10.1021/jm070035a

A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors with drastically improved cardiovascular and neurological profiles.

Full text of DOI:10.1021/jm070035a

1078
J. Med. Chem. 2007, 50, 1078-1082
Brief Articles
N-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy Derivatives as Acetyl-CoA
Carboxylase InhibitorssImprovement of Cardiovascular and Neurological Liabilities via
Structural Modifications
Yu Gui Gu,*,† Moshe Weitzberg,† Richard F. Clark,† Xiangdong Xu,† Qun Li,† Nathan L. Lubbers,‡ Yi Yang,§
David W. A. Beno,| Deborah L. Widomski,‡ Tianyuan Zhang,† T. Matthew Hansen,† Robert F. Keyes,† Jeffrey F. Waring,§
Sherry L. Carroll,| Xiaojun Wang,† Rongqi Wang,† Christine H. Healan-Greenberg,§ Eric A. Blomme,§ Bruce A. Beutel,†
Hing L. Sham,† and Heidi S. Camp†
Global Pharmaceutical Research and DeVelopment, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064
ReceiVed January 10, 2007
A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular
liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker
as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and
1-(S) induced gene expression patterns similar to that seen with several known cardiotoxic agents such as
doxorubicin. Replacement of the alkyne with alternative linker groups led to a new series of ACC inhibitors
with drastically improved cardiovascular and neurological profiles.
Introduction
a higher fatty acid oxidation rate and reduced fat accumulation
compared to their wild type cohorts.12,13 Recently, we reported
a class of novel ACC inhibitors exemplified by 1-(S) (Figure
1).14 1-(S) is a potent and selective ACC2 inhibitor with an
ACC2 IC50 of 38 nM and >1000-fold selectivity against ACC1.
This compound has also demonstrated dose-dependent mCoA
lowering in muscles of rodents with minimal effect on mCoA
levels in liver in an acute setting, consistent with results observed
for ACC2 homozygous knockout mice.12
The increasing epidemic of type 2 diabetes in recent years is
largely attributed to proliferation of key risk factors, which
include a high fat diet, a sedentary lifestyle, and the demographic
shift to a more aged population. It is well accepted that increased
abdominal obesity and physical inactivity contribute significantly
to the development of type 2 diabetes. It is estimated that
approximately 80% of type 2 diabetics are considered obese in
Western societies.1,2
Recently, our colleagues at Abbott demonstrated that an acute
anesthetized rat cardiovascular model is an effective tool to
identify compounds with undesirable cardiovascular and neu-
rological liabilities at an early stage of lead optimization,15,16
and it has been successfully applied to triage melanin-
concentrating hormone receptor 1 antagonists based on cardio-
vascular safety profiles.17 We utilized this rat cardiovascular
model to preliminarily evaluate the safety profiles of our ACC2
inhibitors. A hemodynamic study of 1-(S) in anesthetized rats
using intravenous dosing revealed serious seizure and cardio-
vascular liabilities. We reasoned that because ACC2 knockout
mice have been reported to be healthy and behave normally,
the observed toxic effects of 1-(S) are likely associated with
the chemical structure of this compound, rather than a result of
ACC2 inhibition. Compounds 5a and 5b, two structurally related
yet inactive analogues, provided initial support for this hypoth-
esis. These compounds caused seizures in anesthetized rats at
45 mg/kg and 15 mg/kg, respectively (Table 1). This result
prompted a systematic screen of more than twenty compounds
containing structural variations in different areas of the molecule
to identify the structural motif responsible for the cardiovascular
and neurological side effects.
The pathophysiology of obesity-induced diabetes initiates
when the ability of adipose tissue to store excess nutrients
exceeds its capacity due to increased energy intake. At the
cellular level, this leads to an increase in ectopic fat accumula-
tion in nonadipose tissues such as skeletal muscle, liver, and
pancreas. It has been shown that the level of intracellular lipids
found in skeletal muscle and liver is a strong predictor of the
development of insulin resistance and type 2 diabetes.3,4
Therefore, there has been increasing research interest in the
paradigm of altering lipid disorders by targeting enzymes that
are involved in lipid synthesis and oxidation.5
Acetyl-CoA carboxylases6 (ACCa) play an important role in
lipid pathways via the modulation of malonyl Co-A (mCoA),7,8
a key regulator of fatty acid metabolism. ACC1, a 265 kDa cyto-
solic protein, is primarily expressed in lipogenic tissues (liver
and adipose),9 whereas ACC2, a 280 kDa protein located in the
mitochondrial outer membrane, is highly expressed in oxidative
tissues (muscle, heart, and liver).10 Genetic studies have demon-
strated that ACC1 knockout in mouse is embryonically lethal,11
whereas ACC2 homozygous mice are healthy, fertile, and have
* To whom correspondence should be addressed. Tel.: (847) 937-4792.
Fax: (847) 938-3403. E-mail: yu-gui.y.gu@abbott.com.
† Metabolic Disease Research.
Chemistry
‡ Integrative Pharmacology.
As reported previously,14 the alkyne derivatives 5 were
synthesized from 2 via Sonogashira coupling with 4, followed
by deprotection of the phthalimide group and derivatization of
§ Cellular, Molecular, and Exploratory Toxicology.
| Exploratory Kinetics.
a Abbreviations: ACC, acetyl-CoA carboxylase; mCoA, malonyl-CoA.
10.1021/jm070035a CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/14/2007

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 1079
Gene Expression
The results of the rat cardiovascular study prompted us to
evaluate the effects of various ACC inhibitors on cardiac gene
expression patterns. Male Sprague-Dawley rats were treated
orally with active (S) and inactive (R)14 enantiomers of 1 and
9, respectively, at 100 mg/kg b.i.d dosing for 3 days. Compounds
9-(R) and 9-(S) have virtually identical oral pharmacokinetic
profiles in rat (see Supporting Information). Compound 9-(S)
is a very potent ACC inhibitor with hACC1 IC50 ) 0.020 µM
and hACC2 IC50 ) 0.003 µM, while 9-(R) is a very weak ACC
inhibitor (hACC1 IC50 ) 3.35 µM and hACC2 IC50 ) 0.63
µM). Doxorubicin, an anticancer drug known to induce car-
diotoxicity, was used as a positive control.19 No changes were
observed in serum chemistry parameters or heart histology, other
than mild cholesterol elevation in rats treated with active
enantiomers 1-(S) and 9-(S), respectively. Gene expression
profiles in heart were generated using the Affymetrix RAE230A
microarray platform and were subjected to principal component
analysis, in which the position of the points in space reflects
integrated gene expression profiles derived from each treatment.
As shown in Figure 3A, the gene expression patterns induced
by both (R)- and (S)-enantiomers of 1 were similar to those
induced by doxorubicin, clearly separating from patterns induced
by the active and inactive enantiomers of 9.
Figure 1. Selective ACC2 inhibitor.
the resulting primary amine (Scheme 1). Lithiation of 3, which
was synthesized by reacting 4-isopropoxyphenol with 2-bro-
mothiazole, and subsequent reaction with N-formylmorpholine
produced 6. Compound 6 was sequentially reacted with hy-
droxylamine and N-chlorosuccinimide (NCS) to provide the
corresponding chloroaldoxime, which upon treatment with base
underwent [3+2] dipolar cycloaddition with alkyne 4 to provide
8 regioselectively. Compound 8 was readily converted to 9, as
depicted in Scheme 1. Alternatively, the anion derived from 3
was reacted with tributyltin chloride to provide stannane 7. Stille
coupling of 7 with 2-bromothiazole yielded dithiazole compound
10. Lithiation of the terminal thiazole with n-BuLi and treatment
of the resulting anion with acetaldehyde gave alcohol 11.
Compound 11 was converted to 12 by following a modified
Ritter reaction condition.18
Hemodynamic Studies in Rats
The gene expression changes were also compared to those
present in the Iconix DrugMatrix database, which contains gene
expression profiles of multiple organs of rats treated with over
600 known pharmacological and toxicological agents.20 Figure
3B demonstrates the comparison of gene expression patterns
induced by ACC inhibitors to that found in heart DrugMatrix
database. Compound 1-(R) had strong correlations with a
number of reference expression profiles within DrugMatrix. The
majority of these reference expression profiles are from known
cardiotoxicants or cardiotonic agents, including doxorubicin,
cyclosporine A, haloperidol, dobutamine, and norepinephrine.
Compound 1-(S), to a lesser extent, also had similar gene
expression patterns to the known cardiotoxicants in DrugMatrix.
In contrast, the gene expression profiles induced by 9-(S) and
9-(R) had little or no similarities to the known toxicants. Because
the gene expression changes occurred for both the active and
the inactive enantiomers of 1, the observed cardiotoxicity is most
likely independent of target inhibition.
We also evaluated gene expression changes related to various
biological pathways. The alkynyl compounds 1-(S) and 1-(R)
significantly impacted the expression levels of genes involved
in mitochondrial oxidative phosphorylation pathway, such as
NADH dehydrogenase (ubiquinone), ubiquinol-cytochrome c
reductase, cytochrome c oxidase, and ATP synthase, in a similar
fashion to the known cardiac toxicant doxorubicin, whereas the
nonalkynyl compounds did not.
Hemodynamic studies in anesthetized rats were carried out
to evaluate the preliminary cardiovascular and neurological
safety of ACC2 inhibitors without knowing accurate efficacious
drug concentrations. A screening protocol was established
whereby compound administration was incrementally increased
via 30-minute intravenous infusions at doses of 4.5, 15, and 45
mg/kg to achieve a targeted maximum plasma drug concentra-
tion of approximately 90 µg/mL based on the solubility with
the current series.
Racemic analogues of 1 were screened to quickly identify
any structure motif(s) in the current series, which might be
associated with observed side effects. Variations at both termini
of the molecule did not improve neurological properties in the
series. Introduction of isopropoxy replacements such as cyclo-
propylmethoxy and cyclopropylmethylamino at the left-hand
hydrophobic terminus also produced seizure activity (Table 1,
5c vs 5d and 5e). Similarly, the incorporation of functionalities
such as amide, methyl carbamate, and methylurea at the right-
hand polar end of the molecule did not alter seizure toxicity
profiles (Table 1, 5c, 5f-i). Improvement of the neurological
toxicity profile was finally achieved when the alkyne moiety
was replaced with other linker groups such as five-membered
heteroaryls. Isoxazolyl (9) and thiazolyl (12) analogues exhibited
no seizure effects in the anesthetized rat model (Table 1). These
results indicate that the alkyne linker is responsible for
neurological toxicity within the series.
In addition to neurological toxicity, some of the ACC2
inhibitors in the alkyne series also exhibited adverse cardio-
vascular events. Compound 5c, for example, showed a large,
time-dependent increase (47%) in cardiac contractility (dP/dt)
(Figure 2A). It has been satisfying to discover that replacement
of the alkyne linker with a five-membered heteroaryl group not
only improves neurological toxicity profiles, but also dramati-
cally enhances cardiovascular safety. Compound 9, a direct
nonalkynyl analogue of 5c, showed no adverse cardiovascular
events after escalating intravenous dosing up to 45 mg/kg
(Figure 2B). Similar results were observed with other alkynyl/
nonalkynyl compound pairs (data not shown). Whether the
seizure and adverse cardiovascular effects are interrelated or
caused by independent mechanisms is unknown.
Conclusion
Structure-toxicity relationship studies found the alkyne
moiety to be responsible for the observed neurological and
cardiovascular adverse effects of our lead series of ACC2
inhibitors exemplified by 1-(S). Gene expression profiles in heart
tissues of rats treated with active and inactive enantiomers of 1
(1-(S) and 1-(R), respectively) correlate to those of known
cardiotoxicants. Replacement of the alkyne with alternative link
groups such as heteroaryls dramatically reduces the cardiovas-
cular and neurological liabilities of the series while maintaining
ACC2 inhibitory activity. A full account of the SAR including
the regain of ACC2 selectivity and pharmacological evaluation
of this new series of compounds will be published separately.

1080 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Table 1. Neurological Liabilities of ACC Inhibitorsa
Brief Articles
a The compound was administered in ascending 30 min intravenous infusions at doses of 4.5, 15, and 45 mg/kg in an attempt to reach a maximal plasma
drug level of ∼90 µg/mL, based on known solubility limitations. b The seizure activity was characterized by slight twitching of the limbs with progression
to violent jerking of the head and torso. c Brain/plasma drug level ratio. d The study was terminated prematurely due to severe seizure. e Not determined.
for an additional 30 min, and the precipitate was collected via
filtration and dried to give 2.43 g of the chloroaldoxime as an off-
white solid (82%).
Experimental Section
2-(4-Isopropoxyphenoxy)thiazole-5-carbaldehyde (6). To a
solution of 3 (11.8 g, 0.05 mol) in dry THF was added n-BuLi (20
mL of 2.5 M solution, 0.05 mol) at -78 °C over 15 min. After 1
h, N-formylmorpholine (5.8 g, 0.05 mol) was added dropwise, and
the mixture was stirred for 4 h and then quenched with satd NH4-
Cl. The standard workup and purification on a silica gel flash
column, eluting with 5∼35% ethyl acetate in hexane, provided 13.2
To a solution of the chloroaldoxime (0.31 g, 0.001 mol) and 4
(R ) Me, 0.2 g, 0.001 mol) in toluene was added potassium
carbonate (0.42 g, 0.003 mol), and the reaction was heated at reflux
for 6 h. After cooling to room temperature, the reaction mixture
was diluted with methylene chloride and filtered. The filtrate was
concentrated and purified on a silica gel flash column (eluting with
1
g of 6 as a yellow oil (100% yield). H NMR (300 MHz, CDCl3)
1
10∼30% ethyl acetate in hexane) to give 0.33 g of 8 (70%). H
δ ppm 9.83 (s, 1H), 7.93 (s, 1H), 7.13-7.22 (m, 2H), 6.88-6.98
(m, 2H), 4.46-4.61 (m, 1H), 1.36 (d, J ) 5.88 Hz, 6H). MS (ESI)
m/z: 264.1 (M + H)+.
NMR (300 MHz, CDCl3) δ ppm 7.82-7.94 (m, 2H), 7.69-7.80
(m, 2H), 7.53 (s, 1H) 7.14-7.24 (m, 2H), 6.85-6.97 (m, 2H), 6.51
(s, 1H), 5.67 (q, J ) 7.35 Hz, 1H), 4.41-4.64 (m, 1H), 1.91 (d, J
) 7.35 Hz, 3H), 1.35 (d, J ) 5.88 Hz, 6H). MS (ESI) m/z: 476.0
(M + H)+.
2-(1-(3-(2-(4-Isopropoxyphenoxy)thiazol-5-yl)isoxazol-5-yl)-
ethyl)isoindoline-1,3-dione (8). To a solution of 6 (2.5 g, 0.0095
mol) in pyridine (15 mL, 0.19 mol) was added hydroxylamine
hydrochloride (6.6 g, 0.095 mol) portionwise, and the mixture was
stirred at room temperature for 5 min and then heated at 70 °C for
0.5 h. Water (300 mL) was added, and the mixture was stirred for
20 min. The solid was filtered and dried to give 2.26 g of the
corresponding oxime, which was dissolved in DMF and treated
with NCS (1.17 g, 0.0085 mol). The mixture was stirred at room
temperature for 6 h and water was added. The stirring was continued
N-(1-(3-(2-(4-Isopropoxyphenoxy)thiazol-5-yl)isoxazol-5-yl)-
ethyl)acetamide (9). A mixture of 8 (3.9 g, 0.0082 mol) and
hydrazine monohydrate (4.1 g, 0.082 mol) in 110 mL of methylene
chloride/ethanol (10:1) was refluxed for 3 h. The mixture was
cooled and filtered. The filtrate was concentrated, and the residue
was suspended in methylene chloride and filtered again. The filtrate
was concentrated to give 3.2 g of crude amine, which was dissolved

Brief Articles
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5 1081
Scheme 1a
a Reagents and conditions: (a) Pd(Ph3P)2Cl2 (5% equiv), Cul (2% equiv),
Et3N (5 equiv), THF, reflux, 3 h, 60-80%; (b) (i) NH2NH2 (10 equiv),
CH2Cl2/EtOH (10:1), reflux, 3 h; (ii) Ac2O (3 equiv) (or MeNdCdO for
5g, 5i; MeOCOCl for 1, 5h; and EtCOCl for 5f), Et3N (10 equiv), rt, 3 h,
35-81% (two steps); (c) BuLi (1.05 equiv), N-formylmorpholine (1.05
equiv) for 6 (or Bu3SnCl for 7), THF, -78 °C to rt, 87-93%; (d)
NH2OH‚HCl (10 equiv), pyridine (20 equiv), rt to 70 °C, 95%; (e) NCS
(1.0 equiv), DMF, rt 96%; (f) 4 (R3 ) Me), K2CO3 (3.0 equiv), toluene,
relux, 70%; (g) 2-bromothiazole (0.95 equiv), Pd(Ph3P)4 (5% equiv), DMF,
60 °C, 95%; (h) BuLi (1.1 equiv), acetaldehyde (2.0 equiv), THF, -78 °C
to rt, 83%; (i) BF3‚Et2O (excess), CH3CN, CH2Cl2, reflux, 35%.
Figure 3. Gene expression analysis of rat heart. The rats were dosed
orally (1% Tween in water as vehicle) at 100 mg/kg (bid) for 3 days
and heart tissues were harvested for microarray analysis. Doxorubicin
was used as a positive control. The results were compared with Iconix
DrugMatrix database. (A) Principle component analysis of gene
expression profiles resulting from treatment with 9-(S), 9-(R), 1-(S),
1-(R), and doxorubicin. The three principal components were generated
and plotted for each compound using Spotfire software. Each color
point represents a drug treatment. (B) Correlation of heart gene
expression changes from rats treated with 9-(S), 9-(R), 1-(S), 1-(R),
and doxorubicin with heart gene expression profiles of known cardiac
toxicants within DrugMatrix. Each row represents a single animal
treatment (n ) 3) and each column a reference expression profile in
DrugMatrix. C.C. ) correlation coefficient.
of solvent, the residue was purified on a silica gel flash column,
eluting with 35∼100% ethyl acetate in hexane, to provide 2.34 g
1
of 9 (74%). H NMR (500 MHz, DMSO-d6) δ ppm 8.48 (d, J )
7.54 Hz, 1H), 7.94 (s, 1H), 7.31-7.36 (m, 2H), 6.99-7.05 (m,
2H), 6.88 (s, 1H), 5.06-5.14 (m, 1H), 4.58-4.67 (m, 1H), 1.87
(s, 3H), 1.43 (d, J ) 6.96 Hz, 3H), 1.29 (d, J ) 6.38 Hz, 6H); 13
C
NMR (126 MHz, DMSO-d6) δ ppm 174.89, 168.65, 155.78, 155.17,
147.96, 139.23, 121.77, 118.79, 116.74, 98.45, 69.74, 41.27, 22.41,
21.70, 18.81. MS (ESI) m/z: 388.0 (M + H)+. Anal. (C19H21N3O4S)
C, H, N, S.
hACC1 and hACC2 Assays. See Supporting Information.
Compound Evaluation in Inactin-Anesthetized Rat Cardio-
vascular Assay. Male Sprague-Dawley rats (325-375 g) were
anesthetized with the long-acting barbiturate, Inactin (100 mg/kg,
ip). Catheters (PE-50) were placed in the femoral artery for
measurement of mean arterial pressure and heart rate. A specialized
transducer tip catheter (Millar Instruments Inc., Houston, TX) was
inserted into the left ventricle of the heart for measurement of left
ventricular pressure. The index of cardiac contractility dP/dt50 was
derived from the left ventricular pressure at 50 mmHg. Hemody-
namic data was monitored continuously and acquired at 250 Hz at
a logging rate of every 5 s, which was averaged every minute using
a Ponemah software platform (Gould Instrument Systems, Valley
View, OH). Post-hoc, data was further reduced to 5 min averages
for each rat using a Microsoft Excel spreadsheet application.
Additional catheters were placed in the femoral vein for compound
administration (1-2 mL/kg) and saline infusion (10 µL/min) to
maintain hydration. Escalating doses were given in half log
increments, such that the complete dose was administered by the
end of each 30 min infusion period. The highest dose infused was
Figure 2. Cardiac contractility of 5c (A) and 9 (B) in inactin-
anesthetized rats (n ) 3). PEG-400 was used as vehicle. The plasma
drug levels at the end of the study for both compounds are comparable
(72 and 80 µg/mL, respectively, for 5c and 9, see Table 1).
in methylene chloride. Triethylamine (excess, 2 mL) and acetic
anhydride (excess, 1 mL) were added sequentially at room
temperature, and the mixture was stirred for 0.5 h. After the removal

1082 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 5
Brief Articles
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45 mg/kg. The compounds were dosed using poly(ethylene glycol)
400 (PEG-400) as the vehicle. The cardiac contractility results are
expressed as mean ( SEM (n ) 3 rats per compound).
Gene Expression Analysis. Male Sprague-Dawley rats [Crl:
CD(SD)IGS BR] weighing approximately 200∼250 g were obtained
from Charles River Laboratories, Inc., Portage, MI. The animals
were treated with 100 mg/kg 9-(S) (active), 9-(R) (inactive), 1-(S)
(active), and 1-(R) (inactive) twice daily (b.i.d) by oral gavage for
a period of 3 days and sacrificed on day 4. Vehicle control was
H2O containing 1% Tween. The hearts were snap-frozen in liquid
nitrogen for RNA isolation. Experiments were performed according
to the guidelines established in the National Institutes of Health
Guide for the Care and Use of Laboratory Animals. Frozen heart
samples were immediately added to TRIzol reagent (Invitrogen Life
Technologies, Carlsbad, CA) and homogenized using a Polytron
300D homogenizer (Brinkman Instruments, Westbury, NY). One
mL of the tissue homogenate was transferred to a microfuge tube,
and total RNA was isolated from the TRIzol extracts following
the standard protocol provided by the manufacturer (Invitrogen Life
Technologies, Carlsbad, CA). The quality of total RNA was
monitored using the RNA 6000 Nano Assay with the 2100 Agilent
Bioanalyzer (Agilent Technologies, Palo Alto, CA). The microarray
experiment was performed on Affymetrix RAE230A GeneChip
according to the manufacturer’s protocol, with the exception that
the primer used for the reverse transcription reaction was the
GeneChip T7-Oligo(T) Promoter Primer Kit (Affymetrix, Santa
Clara, CA).
The microarray scanned image and intensity files were imported
into Rosetta Resolver gene expression analysis software version
5.0 (Rosetta Inpharmatics, Seattle, WA). Resolver’s Affymetrix
error model was applied, and ratios were built for each treatment
versus the vehicle controls. Principal components analysis was
completed using Spotfire Decision Site version 8.0 (Spotfire,
Somerville, MA). The similarity of gene expression profiles of the
test compound and reference compounds from the DrugMatrix
database (Iconix Pharmaceuticals, Mountain View, CA) was
calculated as the Pearson’s correlation coefficient based on the
common genes shared by the Affymetrix RAE230A and Codelink
RU1 (GE Healthcare, Piscataway, NJ).
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Acknowledgment. We thank Dr. Xiaolin Zhang, Andy L.
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Supporting Information Available: Synthetic procedures,
analytical and spectroscopic data of the new compounds and key
intermediates in Table 1, as well as 9-(S) and 9-(R), detailed protocol
of human ACC1 and ACC2 assays, pharmacokinetic data of
compounds 1-((), 9-((), 9-(S), and 9-(R). This material is available
free of charge via the Internet at http://pubs.acs.org.
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