1. Image CopyrIght: iSTOCKPHOTO
THE CUTTING EDGE
OF CHEMISTRY
A PHARMA MATTERS REPORT.
APRIL - JUNE 2010
NEW!
Action-packed chemistry review providing insight into the latest
synthesis schemes, scaffolds, mechanisms of action and new
structures advancing drug discovery and development.

2. The Cutting Edge of Chemistry discloses new ideas and achievements in the
biomedical research field with the chemist’s perspective in mind and is a
recently launched addition to the Pharma Matters report series. The report
has been organized into sections that delineate essential aspects of the
search for better and safer drugs.
The Organic Synthesis Scheme Showcase presents a selection of cutting-
edge organic syntheses for drugs currently on the market or in development
worldwide and described in premier publications in medicinal chemistry as well
as in the current patent literature. This section provides access to state-of-the-
art synthetic methods for bioactive compounds, as well as demonstrating how
new synthetic methods lead to interesting intermediates or drugs.
Chemists often start with a novel chemical structure in the drug discovery
process. Molecular scaffolds are the building blocks with which they build
more sophisticated active compounds. Chemists have so far explored only
small regions of the vast molecular universe looking for therapeutic agents,
but are constantly pushing back the frontiers. Scaffolds on the Move relates
efforts in this arena.
Finding new targets to address more selectively is crucial to sustaining a
competitive advantage in pharmaceutical research. Indeed, accurate target
identification and validation processes in the very early stages of any drug
R&D project can make the difference between success and failure in the
clinical application of a new drug as well as a strong intellectual property
strategy. The New Molecular Mechanisms of Action feature highlights this
critical aspect of early-stage research.
The Starting Line includes a series of new molecular entities just entering
the R&D pipeline. Novel, biologically active molecules picked from the
current scientific literature and meetings are revealed in this section. Not
surprisingly, these research projects from industry and academia are the
culmination of the earlier steps in the process: discovery of an original
chemical structure, identification of an appealing new mechanism of action,
and determination of synthetic feasibility.
Thomson Reuters has widely applied in the design of its products and
services the dynamics driving end-user information needs. The Cutting Edge
of Chemistry is the most recent addition to this concept and we expect it
will constitute, together with the existing Pharma Matters reports, a useful
addition to your reading list.
IN THIS ISSUE
1 orgaNIC SyNtheSIS SCheme ShoWCaSe
An exciting entry to a first-in-class ketolide antibiotic known as
EDP-420 has now been scaled up prior to further testing.
4 SCaFFoLDS oN the moVe
Rapid screening with silkworm larvae could speed up drug
discovery and is this issue’s highlight. Also showcased are
leishmaniasis drugs, hypocholesterolemics, and drugs to
combat HIV.
7 NeW moLeCULar meChaNISmS oF aCtIoN
In this issue, we highlight the mode of action of
antimycobacterial agents for tuberculosis with methionine
aminopeptidase-1a inhibitory activity and of antidiabetic
compounds that are inhibitors of insulin-degrading enzyme.
9 the StartINg LINe aND target FoCUS
Biologics are slowly emerging as an interesting and powerful
avenue of drug discovery but still represent only a fraction of
therapies, both launched and potential, compared to small-
molecule organic drugs.
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY
A

3. ORGANIC SYNTHESIS SCHEME:
COST-EFFECTIVE KETOLIDE ENTRY
An efficient large-scale synthesis of EDP-420, a first-in-class
bridged bicyclic ketolide antibiotic drug candidate, offers a cost-
effective entry point to these compounds in just ten steps [1].
EDP-420 (generic name: modithromycin) is a member of a
new class of antibiotics designed by Enanta to circumvent the
resistance problems now seen with traditional macrolides,
penicillins, and fluoroquinolones, which are often ineffective
against certain strains of respiratory pathogens.
EDP-420 is active against Haemophilus influenzae; atypical
organisms, such as Chlamydia pneumoniae, Mycoplasma
pneumoniae, and Legionella pneumophila; and even multidrug-
resistant streptococci. Enanta has demonstrated safety and
tolerability and presented pharmacokinetics results for the
compound in healthy adults [2], with the conclusion that
efficacy trials for respiratory tract infections should be pursued.
EDP-420 is now in phase II clinical trials for the treatment of
community-acquired pneumonia (CAP) [3][4].
The ten-step synthesis to EDP-420 begins with inexpensive
and commercially available erythromycin A 9-oxime, which is
converted to the end product using triacetylation, palladium-
catalyzed O,O-bis-allylation (bridge formation), acid-catalyzed
sugar cleavage, oxime reduction, acetylation, Os-catalyzed
bridge olefin oxidative cleavage, Corey-Kim oxidation, bridge
oxime formation, deprotection, and, finally, purification to yield
multi-kilogram quantities.
When scaling up from the discovery stage, two transformations
required modification of the reaction conditions. The olefin
oxidative cleavage, which had initially been carried out by
ozonolysis, was finally performed employing sodium periodate
and catalytic amounts of osmium tetroxide, conditions that
adapted well to the equipment available at the pilot plant.
The ketolide formation was modified to circumvent the use of
Dess-Martin periodinane at the multi-kilogram scale, for cost
and safety reasons. Hence, a screening for alternative reagents
revealed that the Corey-Kim conditions provided satisfactory
yields and selectivities after a convenient optimization of the
NCS stoichiometry.
INTEGRITY ENTRY NUMBER: 347484
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 1

4. The ten-step synthesis to EDP-420 begins with Synthesis scheme for EDP-420 (Part 1)
inexpensive and commercially available erythromycin
H3C CH3 H3C CH3
A 9-oxime, which is converted to the end product using N N
triacetylation, palladium-catalyzed O,O-bis-allylation OH CH3
HO OAc CH3
AcO
(bridge formation), acid-catalyzed sugar cleavage, N N
CH3 CH3
oxime reduction, acetylation, Os-catalyzed bridge olefin H3C
O O CH3
H3C
O CH3
HO HO O
oxidative cleavage, Corey-Kim oxidation, bridge oxime HO
Ac2O, Et3N
HO
HO HO
formation, deprotection, and, finally, purification to
H3C CH3 DMAP H3C CH3
yield multi-kilogram quantities. O O CH3 O O CH3
O O
CH3 CH3 CH3 CH3
O OH O OAc
(I) H3C OMe H3C OMe
(II)
CH2 CH2
Boc2O, NaOH
HO OH O O Pd2dba3, dppb
Boc Boc reflux
Bu4NHSO4
(IV) (III)
CH2 CH2
H3C CH3 H3C CH3
N N
OH CH3 OAc CH3
AcO AcO
N N
O H3C O O O
H3C
O O CH3 O O CH3
H3C H3C
HO HO
HO
H3C CH3 H3C CH3
HCl O CH3
O O O
CH3 CH3 CH3 CH3
O O OAc
(VI)
(V) H3C OMe
TiCl3
CH2
H3C CH3 CH2
N
CH3 H3C CH3
AcO H3C O N
HN CH3
AcO
O H3C O
O O CH3 N
H3C O H3C O
HO O O CH3
HO Ac2O H3C
H3C CH3 HO
HO
O H3C CH3
CH3 CH3
O
O CH3 CH3
(VII)
O
(VIII) continues...
2 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

5. Synthesis scheme for EDP-420 (Part 2)
continued...
CH2
O
H3C CH3
N H3C CH3
H3C O N
CH3 H3C O
AcO CH3
AcO
N
N
O H3C O
O O CH3 O H3C O
O O CH3
H3C
HO H3C
HO HO
H3C CH3 NaIO4, OsO4 HO
H3C CH3
O
CH3 CH3 O
CH3 CH3
O
(VIII) O
(IX)
NCS, Me2S, Et3N
O
H3C CH3
H3C O N
CH3
AcO
N N
N N
O H3C O
O O O CH3
NH2 H3C
HO
(XI) O
H3C CH3
O
CH3 CH3
1) HCl
O
2) MeOH
(X)
N N
N
O
N
H3C CH3
H3C O N
CH3
AcO
N
O H3C O
O O CH3
H3C
HO
O
H3C CH3
O
CH3 CH3
O
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 3

6. SCAFFOLDS ON THE MOVE:
SILKWORMS AND THE FIGHT
AGAINST MRSA
Antiinfectives, antidiabetic agents, and antiobesity scaffolds
all feature in this edition of The Cutting Edge of Chemistry. A
natural product skeleton from a marine source, almiramide,
has potential against leishmaniasis, while Yale scientists’
synthetic calixarene derivatives could prove useful in treating
HIV. A range of phosphocoumarin analogues are investigated
as targeting pancreatic cholesterol esterase, while a skeleton
linker modification gives Dainippon Sumitomo Pharma a new
lead in regulating low-density lipoprotein. Merck & Co. targets
obesity and diabetes with its MCD inhibitors.
A group at Kitasato University in Tokyo, Japan, gives us
the highlighted skeleton for this issue in the form of the
nosokomycins, which are antibiotics with activity against
methicillin-resistant Staphylococcus aureus (MRSA). Found to
belong to the moenomycin family, they bear the characteristic
unusual sesterterpenoid fragment. The team has used a rather
novel biological approach to early-stage screening for activity
that allowed them to quickly home in on the most active
compounds. Rather than using a conventional agar diffusion
assay based on paper disks, the team used live silkworm larvae.
In vivo studies are plagued with expense and ethical
considerations, particularly at the primary discovery stage.
The use of invertebrates rather than mammals addresses both
considerations to some degree, and researchers have focused
on Caenorhabditis elegans (a nematode worm), the fruit fly
Drosophila melanogaster, and silkworms.
Indeed, the Japanese researchers had previously demonstrated
that a model of silkworm larvae infected with human
pathogenic bacteria followed by injection with a test compound
can reveal whether or not the test substance has antibiotic
activity on the basis of survival of the larvae or otherwise [5][6].
“Several companies in Japan are interested in the silkworm assay
for evaluating or screening antibiotics,” says team member
Hiroshi Tomada, “but it is still at the early stages of development.
We believe that this silkworm system is good for predicting
antibiotic efficacy in vivo, and reducing the number of animals for
drug development.”
4 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

7. FeatUreD SCaFFoLD
SILKY APPROACH TO ANTIBIOTICS
O NH2
Two papers from the Kitasato Institute describe nosokomycins, antibiotics OH O
HO
CH3
O O CH3 CH2
from the broth of Streptomyces sp. K04-0144. They are new members HO OH
H2N O O
OH
P
O
O
H3C CH3
CH3
CH3 CH3
of the structurally rare moenomycin family, which bears an unusual
HO O O
O O O OH
sesterterpenoid moiety. Their identity characteristic is the absence of the H3C
H
N
O
O
OH
O
NH
CH3
cyclopentenone ring present in the oligosaccharide moiety of moenomycin O
O
HO CH3
A. The team used a rather new approach to detecting these compounds by HO
O O
screening microbial culture broths with an in vivo-mimic assay employing HO
OH
OH
silkworm larvae. Activity against MRSA was demonstrated at low doses.
THERAPEUTIC GROUP: MOST RECENT SOURCE:
Antibiotics Uchida, R.; Iwatsuki, M.; Kim, Y.P.;
Ohte, S.; Omura, S.; Tomoda, H.
Nosokomycins, new antibiotics
discovered in an in vivo-mimic
infection model using silkworm
larvae. I: Fermentation, isolation
and biological properties.
J Antibiot 2010, 63(4): 151.
Uchida, R.; Iwatsuki, M.; Kim, Y.P.;
Omura, S.; Tomoda, H.
Nosokomycins, new antibiotics
discovered in an in vivo-mimic
infection model using silkworm
larvae. II: Structure elucidation.
J Antibiot 2010, 63(4): 157.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Kitasato Institute 466456
LIPOPEPTIDE LEAD FOR LEISHMANIASIS
H3C CH3
The protozoal disease leishmaniasis afflicts 12 million people worldwide CH3 CH3 O CH3 O CH3 CH3 O
each year and so represents a major target for new scaffolds. U.S. N
N
N
N
N
NH2
HC
researchers have focused on almiramides A-C, extracted from marine O
H3C
CH3
CH3
O
H3C CH3
CH3 O
cyanobacteria, as they have in vitro activity against the parasite. The
scaffold is an N-methylated linear lipopeptide with an unsaturated
terminus on the side chain that is a requirement for activity. Structure-
activity optimization has led to a new compound from which several
semi-synthetic derivatives with fully methylated peptide backbones and
improved selectivity indices have been obtained.
THERAPEUTIC GROUP: MOST RECENT SOURCE:
Antileishmanials Sanchez, L.M.; Lopez, D.; Vesely,
B.A.; Della Togna, G.; Gerwick,
W.H.; Kyle, D.E.; Linington, R.G.
Almiramides A-C: Discovery and
development of a new class of
leishmaniasis lead compounds.
J Med Chem 2010, 53(10): 4187.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
University of California, Santa Cruz 698465
INDICASAT
Scripps Institution of Oceanography
University of California, San Diego
University of South Florida
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 5

8. NEW LINK FOR CHOLESTEROL-LOWERING COMPOUNDS
Dainippon Sumitomo Pharma describes the extension of work with an
N N up-regulator of low-density lipoprotein receptor (LDL-R) expression, which
is an inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT).
N
H3C CH3 They have replaced the methylene urea linker in their compound with an
H acylsulfonamide linker, which then allowed them to retain potent LDL-R
O N O
S CH3 up-regulatory activity but reduce interference with ACAT even at
O O 1 µM concentration. The sodium salts of the optimized compound reduced
CH3 O
plasma total and LDL cholesterol levels in a hyperlipidemic animal model.
CH3
THERAPEUTIC GROUP: MOST RECENT SOURCE:
Treatment of Lipoprotein Disorders Asano, S.; Ban, H.; Tsuboya, N.;
Uno, S.; Kino, K.; Ioriya, K.; Kitano,
STUDIED MECHANISM OF ACTION: M.; Ueno, Y.
LDL-Receptor Up-Regulators A novel class of antihyperlipidemic
agents with low density lipoprotein
receptor up-regulation via the
adaptor protein autosomal
recessive hypercholesterolemia.
J Med Chem 2010, 53(8): 3284.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Dainippon Sumitomo Pharma 697434
PHOSPHOCOUMARINS TARGET CHOLESTEROL ENZYME
Cl Pancreatic cholesterol esterase (CEase) is a useful target in atherosclerosis
and for the development of hypocholesterolemic agents. A team at Sun
Yat-Sen University has prepared 45 isocoumarin phosphorus analogues,
O
P phosphaisocoumarins, and investigated inhibition of CEase. Three of these
O OH
phosphaisocoumarins displayed a potent inhibitory effect on Cease, with
IC50 values of 4.8, 2.3 and 1.9 µM.
THERAPEUTIC GROUP: MOST RECENT SOURCE:
Treatment of Disorders of Li, B.; Zhou, B.; Lu, H.; Ma, L.; Peng, A.Y.
the Coronary Arteries and Phosphaisocoumarins as a new
Atherosclerosis class of potent inhibitors for
pancreatic cholesterol esterase.
STUDIED MECHANISM OF ACTION: Eur J Med Chem 2010, 45(5): 1955.
Cholesterol Esterase Inhibitors
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Sun Yat-Sen University 696200
MCD INHIBITION KEEPING HUNGER AT BAY
F
Merck discusses a new class of MCD (malonyl-CoA decarboxylase)
H
F F N inhibitors with potential in treating type 2 diabetes and obesity, two
N CH3
HO
S
conditions with the biggest risk of chronic disease and mortality. The
F N O
researchers have focused on the fatty acid intermediate malonyl-CoA
F
F N because of its role in satiety and the fact that inhibition of MCD in the
brain increases levels of the substance. Research in mice has shown
inhibition to lead to a reduction in food intake. Moreover, malonyl-CoA
is also an endogenous inhibitor of CPT-I, a fatty acid oxidation (FAO)
enzyme, and so MCD inhibition may play an additional role in shifting
energy metabolism from FAO to glucose oxidation.
THERAPEUTIC GROUP: MOST RECENT SOURCE:
Antiobesity Drugs; Tang, H.; Yan, Y.; Feng, Z.; De Jesus,
Antidiabetic Drugs R.K.; et al.
Design and synthesis of a new class
STUDIED MECHANISM OF ACTION: of MCD inhibitors with anti-obesity
Malonyl-CoA Decarboxylase and anti-diabetic activities.
Inhibitors 32nd Natl Med Chem Symp (June 6-9,
Minneapolis-St. Paul) 2010, Abst 34.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Merck & Co. 698981
6 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

9. MOLECULAR VASE COMBATS HIV
O O
Yale University scientists report that tetrabutoxy-calix[4]arene derivatives
had previously been shown to be useful oncolytic scaffolds, through HO OH
inhibition of binding of VEGF and PDGFR to their respective receptors.
They now suggest that a modified calixarene might be used as a dual O NH
antiviral strategy in treating HIV and hepatitis C. Mode of action is
O
currently being investigated, but clues regarding structure-activity HO
relationships suggest that interacting head groups may play a key role in H
HO
the dual antiviral effect and that maintaining these at the broader rim of N O O O O
the calixarene cone is essential for activity. O O O
O N
H
THERAPEUTIC GROUP: MOST RECENT SOURCE: OH
OH
Anti-HIV Agents; Tsou, L.K.; Dutschman, G.E.; Gullen, O
Anti-Hepatitis C Virus Drugs E.A.; Telpoukhovskaia, M.; Cheng,
Y.C.; Hamilton, A.D. HN O
Discovery of a synthetic dual
inhibitor of HIV and HCV infection HO OH
based on a tetrabutoxy-calix[4]
O O
arene scaffold.
Bioorg Med Chem Lett 2010, 20(7): 2137.
ORGANIZATION: INTEGRITY ENTRY NUMBER:
Yale University 694442
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 7

10. NEW MOLECULAR MECHANISMS OF ACTION
The mode of action of any product is key to understanding how to improve on any given design and how
to find more potent leads with fewer potential side effects. We notice in the discovery end of the pipeline
for top Pharma companies the therapeutic areas with greatest focus include inflammation, pain, diabetes,
obesity, and bacterial infections. In this issue we highlight the mode of action of antimycobacterial agents
for tuberculosis with methionine aminopeptidase-1a inhibitory activity and of antidiabetic compounds
involving inhibitors of insulin-degrading enzyme.
O
Cl CN CH 3
O
S Cl OH O
O O
S N I H3C N
N S N Cl
H H3C CH3
S Cl CH3 O N O
O CH3
I
UbIqUItIN proteIN LIgaSe m. tUberCULoSIS o. VoLVULUS ChItINaSe eNDopLaSmIN (gp96;
e3 INhIbItorS methIoNINe oVCht1 INhIbItorS gpr94) INhIbItorS
amINopeptIDaSe-1a
(metap1a) INhIbItorS;
m. tUberCULoSIS
methIoNINe
amINopeptIDaSe-1b
(metap1b) INhIbItorS
MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS:
Cancer, Breast Tuberculosis Onchocerciasis Systemic Lupus Erythematosus
ORGANIZATION: ORGANIZATION: ORGANIZATION: ORGANIZATION:
Cardiff University Johns Hopkins University Scripps Research Institute University of Connecticut
Barbara Ann Karmanos School Medicine Korea Res. Inst. Chem. Technol.
Cancer Institute Texas Southern University Seoul National University
DRUG NAME: Closantel DRUG NAME: GPM-1
INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER:
694234 495652 689456 691746
N
H
N
N O O O
H H
HO N N
N .HCl N N NH2
N H H
O O
NH
N
N NH2 O OH
HN H
aCtIVIN reCeptor LIke INSULIN-DegraDINg
kINaSe 3 (aLk3; bmpr-Ia) eNzyme (INSULySIN;
INhIbItorS abeta-DegraDINg
proteaSe) INhIbItorS
MAIN RELATED CONDITIONS: MAIN RELATED CONDITIONS:
Ossification, extraskeletal; Diabetes
Colitis; Anemia
ORGANIZATION: ORGANIZATION:
Massachusetts General Harvard College
Hospital Yale University
Stemgent Brigham & Women’s Hospital
Brigham & Women’s Hospital
DRUG NAME: LDN-193189 DRUG NAME: Ii-1
INTEGRITY ENTRY NUMBER: INTEGRITY ENTRY NUMBER:
642052 668389
8 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

11. THE STARTING LINE AND TARGET
FOCUS: BIOLOGICS MORE PAINFUL
THAN ORGANICS
The Starting Line pinpoints new molecular entities (NMEs)
ready to progress into the R&D arena. This issue’s focus is on
pain and also looks at NMEs for other conditions including
cancer, asthma and trypanosomiasis.
Historically, small drug molecules produced using conventional
organic synthesis techniques have been developed to treat
pain. In recent years drugs from biological sources are receiving
a growing interest within the pharmaceutical industry.
In contrast to conventional drug synthesis, biologics are
manufactured in a living system such as a microorganism,
plant, or animal cell, and are being developed by using a variety
of techniques including recombinant DNA expression.
Organically synthesized small molecules have been extremely
successful, in part due to the well-defined chemical structure.
In many cases, the crystal structure of a small molecule docking
with its protein target can be obtained to reveal the underlying
chemical mechanism of action and to guide modifications that
can lead to more efficacious analogues. Moreover, chemical
analysis and characterization of any components and the
purity of a formulation are relatively accessible using standard
laboratory techniques. In contrast, biologics represent a
much more diffuse proposition and so are far more difficult
to determine using standard laboratory tests. After all, some
of the components of biologic therapies may be unknown,
as post-translational modifications of the biologic can often
generate minor changes in the drug.
Additionally, the living systems used to produce biologics
can be sensitive to minor changes in the conditions of the
production process, potentially causing the final product to
deviate from the known structure significantly and so altering
the way in which it acts in the body. As such the source and
nature of the starting materials, as well as the manufacturing
process, have to be extremely tightly controlled to ensure the
drug is produced as expected.
In the area of pain monoclonal antibodies (MAbs) are an
emerging area of therapeutic research still very much in their
infancy. It is rather telling that within Integrity there are some
230 drugs that are under active development for pain in human
trials. Of these, the overwhelming majority are organically
synthesized molecules, with no more than 5% classified as
MAbs. All the latter act as anti-Nerve Growth Factor drugs.
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 9

12. Thus far no MAbs have been successfully launched for pain.
In June 2010, the FDA requested that trials of the Pfizer drug
tanezumab for treatment of osteoarthritis pain be suspended,
following some concerns around the worsening of osteoarthritis
after taking the drug. In July 2010 trials of tanezumab were
halted for two further indications. This drug is currently in
clinical trials for other forms of pain and is being investigated
with regards to continuing. If launched this will be the first
biotech therapy approved for pain.
In this issue of The Cutting Edge of Chemistry we see three
new molecular entities for treatment of pain, none of which
are biologics and all of which can be chemically synthesized.
However, some observers suggest that one of the limiting
factors in the development of biologics is mainly regulatory.
If there were a smoother route to approval for biologic drugs,
would they become more widespread and provide innovative
therapies for healthcare?
SOURCE DETAILS
N ORGANIZATION: University of LITERATURE:
CH3
Cl
N
Dundee; University of Toronto; Frearson, J.A.; Brand, S.; McElroy,
H University of York S.P.; et al.
H3C N NH
N S N-myristoyltransferase inhibitors
O O PRODUCT: DDD-85646
N Cl as new leads to treat sleeping
CH3 CONDITION: Trypanosomiasis sickness.
Nature 2010, 464(7289): 728.
MECHANISM OF ACTION:
N-Myristoyltransferase Inhibitors
INTEGRITY ENTRY NUMBER:
692017
ORGANIZATION: Merck Frosst LITERATURE:
Colucci, J.; Boyd, M.; Berthelette, C.;
N PRODUCT: MF-766
Chiasson, J.-F.; et al.
N O CONDITION: Arthritis; Pain Discovery of
H
F 4-{1-[({1-[4-(trifluoromethyl)
HO MECHANISM OF ACTION:
F benzyl]-1H-indol-7-yl}carbonyl)
F Prostanoid EP4 Antagonists
O amino]cyclopropyl}benzoic acid
INTEGRITY ENTRY NUMBER: (MF-766), a highly potent and
638300 selective EP4 antagonist for treating
inflammatory pain.
Bioorg Med Chem Lett 2010, 20(12):
3760.
Boyd, M.; Frosst, M.
The discovery highly potent and
selective EP4 antagonists for the
treatment of inflammatory pain.
32nd Natl Med Chem Symp (June
6-9, Minneapolis-St. Paul) 2010,
Abst 35.
H
H2N N ORGANIZATION: Argolyn LITERATURE:
CH3
NH H3C CH3 Bioscience; Medical University of Hughes, F.M.; Shaner, B.E.; May,
O O O
H H South Carolina L.A.; Zotian, L.; et al.
H3C N N N
N N OH Identification and functional
H H PRODUCT: ABS-212
O O O CH3 characterization of a stable,
CH3 CH3 CONDITION: Pain centrally active derivative of the
N OH
CH3 neurotensin (8-13) fragment as a
CH3 INTEGRITY ENTRY NUMBER:
potential first-in-class analgesic.
695716
J Med Chem 2010, 53(12): 4623.
10 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

13. SOURCE DETAILS
F
ORGANIZATION: Amira LITERATURE: F
Pharmaceuticals Stebbins, K.J.; Broadhead, A.R.; F
Baccei, C.S.; et al. O Na
PRODUCT: AM-206 O
Pharmacological blockade of the
CONDITION: Asthma; Chronic O
DP2 receptor inhibits cigarette O N N
obstructive pulmonary disease smoke-induced inflammation,
(COPD); Rhinitis, allergic mucus cell metaplasia, and epithelial CH3
hyperplasia in the mouse lung.
MECHANISM OF ACTION:
J Pharmacol Exp Ther 2010, 332(3): 764.
CRTH2 Receptor Antagonists
Broadhead, A.; Stebbins, K.J.; Stock,
INTEGRITY ENTRY NUMBER:
N.S.; Coate, H.; et al.
691897
AM206, a novel CRTH2 selective
antagonist, inhibits sneezing and
nasal rubs in a mouse allergic
rhinitis model.
Am J Respir Crit Care Med 2010,
181(Abstracts Issue): A4047.
ORGANIZATION: Wyeth LITERATURE:
Pharmaceuticals O’Neill, D.J.; Adedoyin, A.; Alfinito, F
P.D.; Bray, J.A.; et al.
PRODUCT: WYE-103231 N
O
Discovery of novel selective S
.HCl
CONDITION: Pain; Pain, neuropathic norepinephrine reuptake inhibitors: N
O
OH
4-[3-aryl-2,2-dioxido-2,1,3- H
MECHANISM OF ACTION: N
benzothiadiazol-1(3H)-yl]-1- CH3
Norepinephrine Reuptake Inhibitors
(methylamino)butan-2-ols (WYE-
INTEGRITY ENTRY NUMBER: 103231).
695259 J Med Chem 2010, 53(11): 4511.
O O
ORGANIZATION: BIAL LITERATURE: N O
Kiss, L.E.; Ferreira, H.S.; Torrão, L.; HO Cl N CH3
PRODUCT: BIA-9-1067
Bonifácio, M.J.; Palma, P.N.; Soares-
N
CONDITION: Parkinson’s disease da-Silva, P.; Learmonth, D.A. HO Cl
Discovery of a long-acting, O N
MECHANISM OF ACTION: CH3
peripherally selective inhibitor of
COMT Inhibitors
catechol-O-methyltransferase.
INTEGRITY ENTRY NUMBER: J Med Chem 2010, 53(8): 3396.
686182
O H
ORGANIZATION: Kyowa Hakko Kirin LITERATURE: N
Atsumi, T.; Amishiro, N.; Yamamoto, H3C N
PRODUCT: K-454
J.; Nakazato, T.; et al. N
H3C
CONDITION: Cancer Discovery and development of novel H
isoindolinone derivatives as JAK
MECHANISM OF ACTION: CH3
inhibitors. HO
Jak2 Inhibitors; Jak3 Inhibitors
239th ACS Natl Meet (March 21-25, CH3
INTEGRITY ENTRY NUMBER: San Francisco) 2010, Abst MEDI 149.
476783
CH3
ORGANIZATION: Nihon University; LITERATURE: N
H
N N
O
Roswell Park Cancer Institute Chen, M.; Matsuda, H.; Wang, L.; et al.
HN N NH
O N
O
Pretranscriptional regulation of CH3
CH3
PRODUCT: GB-1201 O N HN O NH
Tgf-beta1 by PI polyamide prevents O
H
N N
N
H
N
O
CONDITION: Ulcer, corneal
H
scarring and accelerates wound N
CH3 H3C
O N
CH3 N
CH3
healing of the cornea after exposure
O N O
H CH3
H
MECHANISM OF ACTION: N
N
N
N N O
to alkali. H
N
H
N H3C
TGFB1 Expression Inhibitors
O
H3C CH3 N O
Mol Ther 2010, 18(3): 519.
H
HN N CH3
N
H
INTEGRITY ENTRY NUMBER: O
H3C
N O
690271
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 11

14. SOURCE DETAILS
O
ORGANIZATION: J-Pharma; LITERATURE:
H2N
OH Mitsubishi Tanabe Pharma Oda, K.; Hosoda, N.; Endo, H.; et al.
Cl L-type amino acid transporter 1
O PRODUCT: KYT-0353
inhibitors inhibit tumor cell growth.
N
O CONDITION: Cancer Cancer Sci 2010, 101(1): 173.
Cl MECHANISM OF ACTION:
Drugs Acting on Amino Acid
NH2
Transporters
INTEGRITY ENTRY NUMBER:
690239
F O O
N ORGANIZATION: LITERATURE:
F
F N OH Johnson & Johnson Rabinowitz, M.H.; Venkatesan, H.;
Cl N
H N Rosen, M.; Peltier, H.; et al.
PRODUCT: JNJ-42041935
Structure based design
CONDITION: Anemia and biological evaluation
of benzimidazole HIF prolyl
MECHANISM OF ACTION:
hydroxylase inhibitors for the
Hypoxia-Inducible Factor Prolyl
treatment of anemia.
Hydroxylase Inhibitors
239th ACS Natl Meet (March 21-25,
INTEGRITY ENTRY NUMBER: San Francisco) 2010, Abst MEDI 321.
689991
Cole, P.; Vasiliou, S.; Rosa, E.;
Fernandez-Forner, D.
Medicinal chemistry highlights from
the 239th American Chemical Society
National Meeting & Exposition.
Drugs Fut 2010, 35(6): 503.
paIN targetSCape
Integrity provides an interactive view of targets and associated
drugs across all therapy areas. In this issue we offer a snapshot
of the Integrity Targetscape for pain. The monoclonal antibodies
in development in the field of pain all act on the nerve growth
factor target highlighted here.
SOURCE: Pain Targetscape, Thomson Reuters Integrity [July 2010]
12 PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY

15. aDDItIoNaL reFereNCeS:
[1] Xu, G.; Tang, D.; Gai, Y.; Wang, G.; et al. An efficient large-
scale synthesis of EDP-420, a first-in-class bridged bicyclic
macrolide (BBM) antibiotic drug candidate. Org Process Res
Dev 2010, 14(3): 504.
[2] Jiang, L.J.; Wang, M.; Or, Y.S. Pharmacokinetics of EDP-420
after ascending single oral doses in healthy adult volunteers.
Antimicrob Agents Chemother 2009, 53(5): 1786.
[3] Bermudez, L.E.; Motamedi, N.; Chee, C.; Baimukanova,
G.; Kolonoski, P.; Inderlied, C.; Aralar, P.; Wang, G.; Phan,
L.T.; Young, L.S. EDP-420, a bicyclolide (bridged bicyclic
macrolide), is active against Mycobacterium avium.
Antimicrob Agents Chemother 2007, 51(5): 1666.
[4] Bermudez, L.E.; Motamedi, N.; Kolonoski, P.; Chee, C.;
Baimukanova, G.; Bildfell, R.; Wang, G.; Phan, L.T.; Young,
L.S. The efficacy of clarithromycin and the bicyclolide EDP-
420 against mycobacterium avium in a mouse model of
pulmonary infection. J Infect Dis 2008, 197: 1506.
[5] Kaito, C.; Akimitsu, N.; Watanabe, H.; Sekimizu, K.
Silkworm larvae as an animal model of bacterial infection
pathogenic to humans. Microb Pathog 2002, 32(4): 183.
[6] Hamamoto, H.; Kurokawa, K.; Kaito, C.; Kamura, K.;
Razanajatovo, I.M.; Kusuhara, H.; Santa, T.; Sekimizu,
K. Quantitative evaluation of the therapeutic effects
of antibiotics using silkworms infected with human
pathogenic microorganisms. Antimicrob Agents Chemother
2004, 48(3): 774.
PHARMA MATTERS | THE CUTTING EDGE OF CHEMISTRY 13

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