Professional Documents
Culture Documents
CD8
T cells not only results in costimulation of B cells to produce IgE, but also
in the differentiation of T cells into Th2 cells.
27
Naive CD4
T
c
1 cells predominate over CD4
Th2 cells.
45
There is no increase in eosinophils, mast
cells, or the bronchoconstrictive agents histamine and cysteinyl leukotrienes in COPD.
46
Macrophages are resident in the lungs of COPD patients, but neutrophils and Tcells must migrate from the bone
marrow and lymph node, respectively, to the lung. Like eosinophils and CD4
T cells trafc to inammatory sites through the interaction of VLA-4 and LFA-1 integrins and PSGL-1 with
endothelial adhesion molecules and selectins, respectively. Chemotaxis of CD8
in a manner that bridges two monomeric active sites. The inhibitors reported to
date typically display a symmetrical motif with the following design characteristics: headlinkerscaffoldlinkerhead.
As with the monofunctional analogs they also display an arginine or lysine-like functional group attached to a
heterocyclic core. Analogs 56, 57, and 58 represent such designs.
194
Figure 5 Beta-tryptase tetramer crystal structure with a conceptual bifunctional ligand (blue).
Asthma and Chronic Obstructive Pulmonary Disease 899
O
O
BnO
O
N N
H
O
H
2
N
O
N
N
N
H
O
NH
2
O
N
56 Tryptase K
i
= 1.3 nM
O
O
O
O
H
N
O
H
N
H
2
N
NH
2
57 Tryptase K
i
= 7.5 nM
NH
H
2
N
O
N
H
O O
N
H
O
NH
2
NH
58 Tryptase K
i
= < 1 nM
An analysis of analog 58 illustrates the role played by the amidine moieties play in building the adjacent S1 pocket
interactions. It is subnanomolar in potency and a single change such as exchange of an amidine for a nitrile results in
analogs 2000-fold less potent. The analog possesses excellent selectivity (1 mM, trypsin; 4100 mM, thrombin; 4 mM,
plasmin) and has been shown to be efcacious when delivered intratracheally at 1 mg kg
1
in a guinea pig airway
hyperresponsiveness screen. This is an important point as the bifunctional inhibitors are limited to powder inhalation
formulations given their generally poor pharmacokinetic properties. Another way to exploit the bifunctional concept
toward inhibitor design is illustrated by analog 59. In this example the smaller monofunctional monomer can form a
dimeric species through hydrogen bonding of the primary amide group. The SAR shows that a charged acid species is
essentially inactive while the corresponding ethyl ester exhibited only modest potency (K
i
88 and 59 mM,
respectively).
195
When compared to the dimers linked by a covalent bond, the pseudodimeric associative approach may
offer some advantages in terms of molecules with lower molecular weight, better solubility, and improved
pharmacokinetic properties.
N
O
H
2
N
N
N
O
S
59 Tryptase K
i
= 1.5 nM
R
NH
2
O
R = F versus H increases hERG activity
(17 versus >30 mM)
Amide >> acid > ester
Bifunctional binding mode Dimeric binding mode
versus
The last strategy involves the concept of tetramer disruption. Although controversial, it is believed that dissociation
of the heparin-stabilized tryptase tetramer into monomeric units results in irreversible inactivation of the enzyme. It
has been shown that the heparin antagonists polybrene (IC
50
3.6 nM) and protamine (IC
50
65 nM) are both
potent inhibitors of human lung tryptase either competitively or noncompetitively.
196
Protamine is an arginine-rich
polycationic protein which is involved in DNA binding in spermatozoa, and it has been used clinically as a heparin
900 Asthma and Chronic Obstructive Pulmonary Disease
antagonist to reverse the effect of injected heparin during surgery. Other examples of inhibitors are lactoferrin, which is
a cationic, neutrophil-derived protein of 78 kDa which possesses unique heparin-binding domains, as well as the similar
cationic protein myeloperoxidase (118 kDa).
197
Chymase is classied as a chymotrypsin-like serine protease. Human
chymase is restricted to mast cell populations and is abundant in the skin and submucosal tissue of the respiratory and
gastrointestinal tracts.
198
It is stored along with tryptase in secretory granules but is released as a macromolecular
complex with carboxypeptidase and proteoglycans in response to immunological stimuli. The enzyme complex has an
extended substrate binding site that prefers a phenylalanine residue at pocket P1 and hydrophobic residues at P2 and
P3 in the catalytic cleft. This confers a somewhat broad spectrum of activity including degradation of extracellular
matrix proteins (tissue remodeling) and the synthesis of angiotensin-2. These features suggest that inhibition of
chymase could also provide therapeutic benet in cardiovascular disease.
199
The design of early inhibitors used a
traditional strategy targeting inhibition through substrate mimicry. These early peptides and peptidomimetics were
designed to be recognized by the enzyme and contained a activated functional substituent such as a carbonyl group
made susceptible to nucleophilic addition by the active site Ser195 hydroxyl group.
Several typical examples illustrate the different types or reactive moieties utilized. In general, a-haloketones,
aldehydes, boronic acids, and phosphonate esters can all provide the electrophilic component necessary for reversible
covalent interaction. The reader is referred to the appropriate references and reviews since this is a general,
well-established protease inhibition strategy.
200,201
O N
H
N
H
N
O
O O
O
F
F
N
H
O
CO
2
H
60 Example peptide-'warhead' inhibitor
chymase K
i
= 5.6 nM
Electrophilic center
N
N
H
2
N
O
OMe
NH
O
O
O
N
CO
2
Me
61 Example peptidomimetic
chymase K
i
= 4.8 nM
Despite excellent potency, the therapeutic use of peptide-based inhibitors is still limited due to poor bioavailability.
Reports on nonpeptidic inhibitors are somewhat limited and this is currently an active area of research. An example is
illustrated by the continued renement of analog 60 to furnish 61, which demonstrates that the combination of an
arylpyrimidone scaffold representing P2P3 interactions and the use of a heterocyclic ketone can rival potency while
offering good PK, selectivity, and bioavailability.
202,203
The arylpyrimidone scaffold has spawned a host of inhibitors
whereby researchers have mixed and matched pocket SAR information from peptide programs with a variety of
electrophilic warheads.
204,205
The b-lactams 62 and 63 also diverge from the traditional peptide SAR.
62 Chymase K
i
= 6 nM
N
O
O
HN
OMe
OMe
O O
S
N
N
N
N
CO
2
H
O
63 Shionogi BCEAB
Chymase K
i
= 4 nM
Cat G IC
50
= 35 nM
N
O
HN
O
O
CO
2
H
OEt
Development of a high-throughput screening hit originating from an antibacterial program lead to the discovery of
62, which offers high potency and is somewhat selective over a panel of proteases.
206
A related analog, 63, falls within
Asthma and Chronic Obstructive Pulmonary Disease 901
this compound class and, as expected, the active site Ser195 hydroxyl group is thought to attack the b-lactam carbonyl
leading to ring cleavage and acylation of the enzyme.
207
Analog 64 represents an emerging scaffold with a novel ketophosphonate moiety that offers potency for chymase
and also has been shown to inhibit another mast cell serine protease, cathepsin G (which plays a role in the activation of
PAR-4 leading to platelet activation).
200
Worth noting is the observation that the b-lactam 63 is also reported to have a
similar dual-target specicity demonstrating a cathepsin G in vitro potency of 35 nM. It has been shown that dual
inhibition or selectivity for either serine protease can be modulated through SAR modications at a related specicity
pocket in the active site.
64 Johnson & Johnson
Chymase K
i
= 2.3 nM
Cat G K
i
= 38 nM
N
O
N
O
O
P
OH
O
OH
Recent reports indicate that 64 is advancing to the clinic and has demonstrated in vivo efcacy in preventing
both early- and late-stage airway hyperreactivity in the sheep model at 0.1 mg kg
1
(twice daily aerosol dosing).
For completeness, a brief survey of additional classes of chymase inhibitors is illustrated by structures 6567 below.
205
Each exhibits a unique selectivity prole over related proteases and their optimization has been driven by structure-
based design.
N
N
S
CO
2
H
65 Chymase IC
50
= 1 nM
HO
2
C
O
H
N
S
O
O
66 Chymase IC
50
= 17 nM
S
F
S
HN
O
O
O
N
CO
2
H
67 Chymase IC
50
= 2 nM
Overall, mast cells and mast cell degranulation products play a critical role in modulation of the immune system.
Based on a variety of biological studies, b-tryptase appears to be best associated with a variety of allergic disease states
including asthma. Recent advances in the design of effective inhibitors has been driven by a solid understanding of
enzyme structure and the monofunctional series of analogs seems to hold the most promise. The bifunctional series is
the result of clever exploitation of the enzymes tetrameric structure, however, these molecules may suffer from
downstream development issues based on physicochemical properties. The development of chymase inhibitors has also
taken a structure-guided approach, since many analogs are peptide or peptidomimetic in nature thus taking advantage
of active site catalytic residues in order to covalently inactivate the enzyme. The physiological and pathological roles of
chymase are still to be fully elucidated and are an active area of research. Priority efforts are aligned to this need to
establish validation for the involvement of chymase in both cardiovascular and autoimmune diseases. In general, the
role of mast cell proteases is still under active investigation and the greatest challenge is to design and deliver a
selective, orally available inhibitor with robust efcacy.
7.30.7.5 Interleukin-5 (IL5) Receptor Inhibitors
Pronounced eosinophilic inltration is believed to play a crucial role in the pathogenesis of asthma. The cytokine
IL5 is produced by activated T cells, mast cells, and eosinophils, and functions as a promoter for the proliferation
902 Asthma and Chronic Obstructive Pulmonary Disease
of bone marrow precursor cells and their subsequent differentiation into mature basophils and eosinophils.
208
IL5 also has been shown to promote eosinophil survival and activation during allergic inammation. The high
afnity receptor for IL5 consists of two subunits (a- and b-chain) with the a-chain being the specic or unique
IL5 binding subunit in low afnity and the b-chain assisting in the formation of a high-afnity state receptor
through interaction with the a-chain. In this arrangement, the b-chain is shared by two other receptors, GM-CSF
and IL3.
211
As a method of target validation, it has been shown that wild-type mice treated with an anti-IL5 neutralizing
antibody or IL5
/
genetic knockouts
209
are able to suppress eosinophil recruitment to the lung and inhibit airway
hyperresponsivness to antigen challenge. While animal studies using the antibody approach were encouraging, human
clinical trials with mild atopic asthmatics did not show consistent effects on lung function despite a marked
suppression of circulating eosinophils in the blood. Currently this study design and resulting data has sparked a vigorous
debate on the role of both IL5 and eosinophils, in general, in the pathogenesis of asthmatic disease.
210
Nevertheless,
this level of target validation has generated the interest of medicinal chemistry and the search for small molecule
inhibitors of the IL5 receptor has received some attention. Analog 68 was shown to inhibit binding of IL5 to its
receptor on peripheral human eosinophils.
212,213
Given the lack of published, advanced data and modest potency, this
compound may have simply been used as a research tool to validate the targets signaling pathway through the JAK
kinase manifold.
MeO
MeO
N
N
N
68 YM-90709
Receptor binding IC
50
= 1 M
N
S
O
69 Isothiazolone chemical probe
Receptor binding IC
50
= 20 M
N
Receptor Cys66-SH
(Domain 1)
Another early exploratory approach has identied a class of compounds shown to covalently modify the receptor.
A series of isothiazolones (69) were shown to specically inhibit the IL5/IL5R interaction at the a-chain. This was
veried through the generation of a Cys66 alanine mutant that still bound IL5, which was not disrupted in the
presence of the probe molecule.
214
While not therapeutic drugs, these molecules illustrate that inhibition of the
receptor is chemically tractable. High-throughput screening has also uncovered several other compound classes that
can modulate IL5 binding. Several other irreversible ligands have been identied employing a surface plasmon
resonance/mass spectrometry afnity experiment. Analogs 70 and 71 are moderately active at the IL5 receptor and
were cross-reactive with the IL3 and GM-CSF receptors.
215
SMe
NHEt
OH
70 Chemical probe
Receptor binding IC
50
= ~8 M
N
S
HO
N
71 Chemical probe
Receptor binding IC
50
= ~11 M
Again, druglike molecules were not identied in this study. The probes furthered the understanding of receptor
function with regards to a shared b-chain. Included in this section is a series of recent compounds that have
been demonstrated to inhibit the production of IL5, rather than specically target the receptor. The azauracil
derivative 72 has demonstrated in vitro potency by inhibition of IL5 protein in activated human whole blood and in
isolated human peripheral blood monocytes as well as mouse splenocytes.
216
Message levels for other cytokines
remained unchanged.
Asthma and Chronic Obstructive Pulmonary Disease 903
72 R146225
hWhole blood IC
50
= 34 nM
hPBMC IC
50
= 24 nM
Murine splenocytes IC
50
= 6 nM
N
N S
Cl Cl
Cl
N
N
O O
73 Whole blood IC
50
= 78 nM
MCP-1 IC
50
= 220 nM
MCP-2 IC
50
= 580 nM
MCP-3 IC
50
= 80 nM
S
N
Cl
Cl
N N
O
O
O
O
HO
Since the observed potency was sufcient to test in vivo, the compound showed efcacy at 0.62.5 mg kg
1
orally in
a mouse model measuring pulmonary accumulation of eosinophils. It was found that chronic dosing in pregnant rats and
rabbits induced signs of teratogenesis and further development was halted. This triggered further SAR activity with an
objective to eliminate this adverse effect through the design of an inhaled prodrug as illustrated by analog 73. After a
survey of functionality, it was found that the hydroxypropyl ester offered high metabolic stability in lung tissue while it
was rapidly metabolized to the inactive carboxylic acid by human liver preparations.
217
This effectively translated to
low and short-lived plasma levels of 73. The activity prole suggested that the analogs might target Th2 cells given the
reduced levels of the chemotactic ligands MCP-1,2,3 as well as IL4. In vivo activity was demonstrated by intratracheal
administration of an aerosol in the Ascaris sheep model. Efcacy was seen whether the compound was dosed pre- or
post-antigen challenge with complete abrogation of the late phase response as well as reduced bronchial hyperreactivity
to inhaled carbachol.
Several approaches targeting the cytokine IL5 have been investigated using a variety of strategies in the past
years.
218,219
These include antibody approaches toward the receptor, small-molecule probes to inhibit ligand binding to
the receptor, and agents that prevent production of the cytokine itself. Given the dearth of small-molecule research in
the area, perhaps spawned by the failure of antibodies in the clinical setting, may lead one to conclude that given
asthma has a multifactorial pathogenesis, inhibition of a single signaling agent may not be sufcient for therapy.
7.30.7.6 Inhibition of Leukotriene Biosynthesis
The past decade has witnessed an explosion of activity in the eld of inhibition leukotrienes and outstanding,
comprehensive reviews are available to the reader.
88
Several intersections for intervention in the arachidonic acid pathway
have resulted in a rich history of chemotypes and strategies that an entire volume could be devoted to the discussion.
The following targets best represent these intersections: inhibitors of 5-lipoxygenase (5-LO), inhibitors of the redox
protein, ve lipoxygenase activating protein (FLAP), the leukotriene receptor LTD
4
(CysLT1), and LTB
4
. There has
been interest on other pathway enzymes with limited reports of small molecule research targeting LTA
4
hydrolase.
5-Lipoxygenase is a dioxygenase that incorporates molecular oxygen into arachidonic acid giving rise to the metastable
epoxide LTA
4
. Further processing by either LTA
4
hydrolase (neutrophils and monocytes) or LTC
4
synthetase (mast cells
and eosinophils) generated either LTB
4
or the cysteinyl leukotrienes LTC
4
, LTD
4
, and LTE
4
(Figure 6).
Intervention of 5-LO at the start of the cascade has been an intense area of research since its discovery in
1983.
220,221
Although an attractive target, there has been some concern about possible unwanted side effects especially
since an entire metabolic process would be interfered with. Some genetic knockout information is available and the
mice appear to develop normally.
222
In the design of inhibitors, many researchers targeted the active site, nonheme iron
atom and built in a weak chelator such as a hydroxamic group as best illustrated by Zyo (74, zileuton, Abbott).
223
74 Zileuton (Abbott)
hWhole blood IC
50
= 700 nM
S
N
HO NH
2
O
75 hWhole blood IC
50
= 80 nM
O
O
F
N
HO
O
NH
2
76 Atreleuton (Abbott)
hWhole blood IC
50
= 150 nM
S
F
N
HO
O
NH
2
904 Asthma and Chronic Obstructive Pulmonary Disease
Further structural modications following this design strategy generated the second-generation iron ligand
inhibitors 75 and 76.
224226
The objective of the advanced analogs was to improve potency and to improve duration
of action by inhibition of glucuronidation rate.
224
Analog 76, as the (R)-isomer, provided sustained ex vivo duration of
5-LO inhibition (as measure in a human whole blood assay) and progressed to the clinic with discontinuation after
phase III trials due to elevated liver enzymes. It was about vefold more potent that zileuton in animal models of
bronchospasm and had an oral half-life of B16 h.
Cys
Gly
Glu
COOH
OH
LTD
4
receptor
antagonists
LTE
4
Dipeptidase
LTD
4
LTC
4
-Glutamyl Transpeptidase
LTC
4
synthetase
Metabolism to peptidyl leukotrienes
LTA
4
Mediator of informations
leukocyte recruitment
and activaton
LTB
4
receptor
antagonists
Peptidyl leukotrienes
Mediators of allergy,
bronchoconstriction and
vascular permeability
Metabolism to leukotriene B
4
LTA
4
hydrolase
5-lipoxygenase
dehydration step
AA interacts with 5-lipoxygenase activating protein
(FLAP) 5-Lipoxygenase translocates to the nuclear
membrane where FLAP, AA and 5-LO interact
resulting in oxidative catalysis
5-lipoxygenase
oxidation step
5-LO Inhibitors
FLAP Inhibitors
Arachidonic acid
Phospholipases cleave arachidonic acid from
esterified phospholipids in membrane in reponse
to receptor-mediated intracellular influx of Ca
2+
Cell membrane phospholipids
COOH
COOH
OOH
COOH
O
5-HPETE
COOH
Cys-Gly
COOH
OH
Cys
COOH
OH
OH OH
Figure 6 Leukotriene inammatory pathway and key points of therapeutic intervention. (Reprinted with permission from
Brooks, C. D. W.; Summers, J. B. J. Med. Chem. 1996, 39, 2629 & American Chemical Society.)
Asthma and Chronic Obstructive Pulmonary Disease 905
A unique approach is represented by analog 77 which combines two concepts that could prove benecial in allergy
and asthma.
227
A series of N-hydroxycarbamates containing a histamine H1 antagonist pharmacophore was constructed
and exhibited the desired dual activity prole. Preclinical work in the guinea pig OVA model showed 77 to have a
better overall prole that a traditional 5-LO analog such as 74. Other dual target strategies have been employed
including COX-/5-LO, PAF/5-LO, and lipid and sugar metabolism enhancers/5-LO, although little is reported in the
medicinal chemistry literature. Beyond this approach, the set strategy has been to explore lipophilic groups and linkers
stemming from a terminal hydroxyurea moiety and many examples exist in the review articles. Several isosters of
hydroxyureas have been devised (e.g., analog 78)
133,228
offering modest potency; however, second-generation substrate
inhibitors emerged that were designed to t the 5-LO active site without the need for an iron-chelating group.
Analogs 79 and 80 represent ongoing discovery efforts in this area.
229231
N
N
F
F
O
N
OH
NH
2
O
77 Dual H1/5-LO inhibitor
H1 binding IC
50
= 3.6 nM
hWhole blood 5LO IC
50
= 89 nM
78 Rat basophil leukemia cell IC
50
= 60 nM
N O
HO
Iron chelation
O
OMe
N
S
N
O
O
OMe
F
O
Representative 5-LO substrate inhibitors
79 ZD-2138 (Zeneca)
hWhole blood LTB4 IC
50
= 24 nM
O
O
OMe
N
O
O
F
N
80 CJ-13454 (Pfizer)
hWhole blood LTB4 IC
50
= 34 nM
NH
2
O
The rst to be evaluated in the clinic was analog 79 in a 1-month safety study. A single dose (350 mg orally) was
shown to completely inhibit LTB
4
production in ex vivo blood samples. Phase II studies were designed as allergen
challenge in asthmatics using 79 at the same does. No effect was seen on both early and late stage response, however
identical ex vivo efcacy was seen. After several additional studies development was ultimately stopped. As a follow-on,
the imidazole analog 80 has illustrated improved pharmacokinetic and toxicology characteristics though clinical efcacy
remains to be seen.
FLAP inhibitors comprise a class of compounds that can inhibit leukotriene biosynthesis without direct inhibition of
5-LO. The indomethacin derivative 81 proved indispensable in the discovery of FLAP and understanding the
differential activity observed in intact versus lysed cell results on leukotriene biosynthesis.
232
While the precise
mechanism of action is not clearly understood, FLAP is hypothesized to be essential for activation of 5-LO through
assisting in either the membrane translocation process or as a vehicle for presentation of arachdonic acid. A series
of rst-generation (81, 83) and second-generation (82, 84) inhibitors were discovered and developed in the early to
mid-1990s.
233
By combining pharmacophoric regions of the rst-generation lead compounds researchers were able to
further optimize analog potency. A key observation was the conserved quinoline moiety which turned out to be a
prominent binding motif in many FLAP SAR programs.
906 Asthma and Chronic Obstructive Pulmonary Disease
81 MK-886
Binding IC
50
= 23 nM
N
Cl
CO
2
H
S
N
O
Cl
CO
2
H
S
N
82 MK-591
Binding IC
50
= 2 nM
O
N
CO
2
H
84 BAY-x1005 83 REV-5901
O
N
OH
A number of clinical trials were initiated with varied results. Compound 81, when dosed at 500 mg orally in
asthmatic patients prior to antigen challenge improved both early and late response by 58% and 44%, respectively, but
was discontinued based on the modest leukotriene inhibition measured ex vivo.
234,235
The second-generation analog 82
demonstrated better early and modest late phase response (79% and 39%, respectively) and the ex vivo inhibition of
leukotriene biosynthesis was 98% on ionophore challenge of whole blood up to 24 h. This demonstrated the clinical
efcacy of FLAP inhibition; however, larger studies showed that patient respiratory improvement was not aligned with
in vitro compound potency.
233
To date, no clinical candidate from these programs has emerged to the market. From a
medicinal chemistry point of view, optimization strategies including oxime insertion proved fruitful as illustrated by
analog 85 which provided the desired improvement in solubility and absorption properties.
236
85 Oxime insertion analog
hPMNL LTB
4
inhibition IC
50
= 15 nM
In vivo ED
50
= 0.5 mg kg
1
O
N
O
84 BAY-x1005
N
CO
2
H
86 Symmetrical core analog
hPMNL LTB
4
inhibition IC
50
= 20 nM
In vivo ED
50
= 1.5 mg kg
1
O
N
O
N
CO
2
H
O
N
R
R = H or Me
Further renement, as demonstrated by the symmetrical core analog 86, removed the stereocenter (which proved too
costly to develop) yet maintained superior potency in inhibiting LTB
4
formation in human neutrophils challenged with a
calcium ionophore. Given the efcacy in rodent asthma models, analog 86 progressed to phase I clinical trials.
237,238
The best-represented compounds in the area of LTD
4
(CysLT1) inhibition are the marketed drugs Singulair
(montelukast, Merck),
90,239
Accolate (zarlukast, AstraZeneca),
89,240
and Ultair (pranlukast, Ono).
241
The history of
the development of these drugs is a fascinating story and stems from SAR and privileged pharmacophores identied in
5-LO and FLAP research programs. Most importantly it was the seminal discovery that the active components of slow-
reacting substance of anaphylaxis (SRS-A) were the CysLTs, specically LTD
4
, LTC
4
, and LTE
4
.
242,243
This, coupled
with the strong evidence that SRS-A played a pivotal role in bronchoconstriction launched intense research efforts. The
resulting analogs generally comprise combined lipid, acid, and peptide mimetics representing the three key regions and
stereochemistry of LTD
4
.
Montelukast (88) represents a second-generation inhibitor stemming from its congener 87 which was designed
by combining the FLAP active quinioline pharmacophore with a thioacetal unit found in early high-throughput
screening hits.
244,245
Asthma and Chronic Obstructive Pulmonary Disease 907
N Cl
S
S
CO
2
H
CON(CH
3
)
2
87 Verlukast (Merck)
Binding IC
50
= 0.8 nM
N Cl
S
S CO
2
H
HO
88 Singulair (montelukast, Merck)
Binding IC
50
= 0.5 nM
Verlukast was in early clinical trials and only demonstrated about a 13% improvement in lung function following a
single oral or aerosol dose. The compound was ultimately withdrawn due to liver function abnormality. Replacement of
one of the thioacetal side chains with an arylalkyl moiety and installation of the geminal cyclopropane substituent
furnished the potent analog 88 which was devoid of undesired side effects especially peroxisomal enzyme induction
which had plagued the rst generation series. In moderate asthmatics, a single 100 mg dose produced an immediate
10% improvement in base line FEV
1
which stayed constant during a 9-h study. Pranlukast (89) and zarlukast (90)
were developed using similar strategies.
89 Pranlukast (Ono)
Binding K
i
= 46 nM
O
NH
O
O
O
N
N
N
H
N
90 Zafirlukast (AstraZeneca)
Binding K
i
= 0.5 nM
N
N
H
O
O
O
H
N
S
O
2
MeO
Analog 89 was identied from a weak high-throughput screening lead and was developed with a strategy that
involved replacement of a benzoic acid moiety with the chromone carboxylate core which increased potency 100-fold.
Subsequent replacement of the carboxylate with a tetrazole isostere furnished both in vitro and in vivo potency
increases. Finally, optimization of the lipophilic tail resulted in the clinical candidate that was approved in Japan in 1995
and was the rst LTD
4
(CysLT1) antagonist to be commercially available.
246,247
The discovery of zarlukast (90) is the subject of several excellent SAR review articles.
248,249
The indole-based
inhibitor was essentially developed by a hybridization between a leukotriene pharmacophore based on LTD
4
itself and
a hydroxyacetophenone series of antagonists found in a screening exercise. Early analogs suffered from pharmacokinetic
issues and poor bioavailability (o1%). Continued optimization of the SAR furnished the clinical candidate that
demonstrated a 117-fold shift (within 2 h) of the doseresponse curve using the LTD
4
induced bronchoconstriction
challenge in asthmatics and was effective in blocking a variety of environmental asthmatic triggers. Zarlukast was the
rst leukotriene modulator approved in the USA, which was then followed by montelukast.
Currently research has slowed in this area and it appears no new agents are being developed. This most likely is
because the market is saturated and these agents are still used in combination therapy with steroids and b-agonists as a
primary care standard for asthma. There has been some controversy over the effectiveness of these agents in the
general population and that still remains to be resolved. Current clinical work is focused on their use for other modes of
inammatory disease such as atopic dermatitis, aspirin- and exercise-induced asthma, as well as seasonal allergic
rhinitis.
The discovery of LTB
4
antagonists has been slower that of the LTD
4
(CysLT1) antagonists. Pharmacological
interest has focused on the proinammatory properties of this lipid mediator that is produced by several cell types
including neutrophils and macrophages. LTB
4
has also been shown to stimulate degranulation and chemotaxis of
inammatory cells through a receptor-based mechanism. Recently the distribution of LTB
4
receptors in human
hematopoietic cells has been studied and it was shown that it is widely distributed and also plays a role in endothelial
cells but not platelets.
250
A variety of diverse chemotypes have been discovered in the past decade with few new
reports since the mid-1990s. Two fundamental research strategies toward drug design have emerged, one based on the
discovery of a key fragment and the other based on mimicking the structure of LTB
4
.
908 Asthma and Chronic Obstructive Pulmonary Disease
O OH
Et
O N
NH
N
N
91 Binding IC
50
= 85 nM (human neutrophils)
O OH
Et
O
N
N
Et
CO
2
H
O
92 Binding IC
50
= 300 nM (human neutrophils)
Replace with OCH
3
IC
50
= 6 nM
OEt IC
50
= 4.8 nM
A key pharmacophore was found, along with some fundamental SAR resulting in various derivatives based on the 5-
ethyl-2,4-dihydroxyacetophone moiety which was hypothesized to be a mimetic of the triene moiety in LTB
4
. Two such
examples are illustrated by analogs 91 and 92.
251253
The location of the alkyl chain of 91 proved critical to selectivity
over LTD
4
. Further SAR work optimizing chain length, carboxy isosteres, and aryl SAR ultimately drove binding potency
down to 4.8 nM and afforded a potent analog that was active in blocking LTB
4
-induced bronchoconstriction in vivo.
Several reviews have been published that are devoted to analogs derived from the parent leukotriene structure.
254
N
H
O
OMe
93 Binding IC
50
= 17 nM (human neutrophils)
NH
N N
N
Replace with CO
2
H IC
50
= 70 nM
94 Binding IC
50
= 6.4 nM (human neutrophils)
O
OH
CO
2
H
Two recent leukotriene-like examples are illustrated by analogs 93 and 94.
255,256
Both the biaryl and carboxy (or
isostere) functionality are required for potency and the design concept is based on a rigid platform with key
functionality appropriately displayed. Analog 94 demonstrated high afnity for the LTB
4
receptor and for related cell
responses. Oral administration in the guinea pig at 3 mg kg
1
blocked 75% of neutrophil response to 12-R-HETE
challenge. Phase I studies used ex vivo inhibition of LTB
4
-induced CD11b in healthy subjects. The analog produced a
10-fold shift in the dose response curve and was well tolerated up to 640 mg kg
1
. Due to its exceptionally long
half-life (t
1/2
420 h) it was discontinued for development.
257
Overall, clinical success has yet to be achieved with this
class of antagonists. It is not clear whether the receptors response to LTB
4
is exclusive or subject to stimulation
by other more potent chemoattractants or whether the primary role of LTB
4
may be coupled with binding to the
BLTR2 receptor.
A key enzyme in the biosynthesis of LTB
4
is LTA
4
hydrolase, which is a zinc-containing metalloenzyme and is
involved in the rate-limiting step for the production of LTB
4
through the hydrolysis of the epoxide moiety. Many early
analogs were dipeptidic in nature as illustrated by the kelatorphan analog 95.
258
N
H
O
HO
O
CO
2
H
Kelatorphan
LTA
4
hydrolase IC
50
= 5 nM
Aminopeptidase IC
50
= 7 nM
NEP IC
50
= 46 nM
ACE IC
50
= > 10 M
N
H
O
HO
O
N
95
LTA
4
hydrolase IC
50
= 8 nM
Aminopeptidase IC
50
= 10 nM
NEP IC
50
= 17 M
ACE IC
50
= 40 M
CO
2
H
Asthma and Chronic Obstructive Pulmonary Disease 909
A systematic study of the peptide and substituent SAR demonstrated that potent compounds could be derived with
selectivity against NEP and ACE could be gained. Overall, the analogs retained their aminopetdidase activity. In all
cases the hydroxamic moiety was required to retain inhibitory activity.
More recently a series of nonpeptide nitrogen heterocycles have been described that are effective inhibitors of LTA
4
hydrolase. They are unique in that they do not appear to bind zinc as the hydroxamic acid inhibitors do and unlike the
peptide, they demonstrate good oral bioavailability. Analogs 96, 97, and 98 illustrate the SAR of this class.
259
O N
Me
CO
2
H
96 SC-57461A
Hydrolase IC50 = 2.5 nM
N
CO
2
Et
O
97 SC-56938
Hydrolase IC
50
= 3 nM
98 Hydrolase IC
50
= 0.8 nM
N
O
N
N
CN
As can be seen in the examples, increased potency can be obtained through optimization of the amine or
heterocyclic component. The series produced two clinical candidates that were chosen based on ex vivo versus in vitro
potency using blood samples. The primary candidate was 96 that was designed through a series of iterative steps
exploring chain length and linker substitution as well as amine substitution. Besides potency in the enzyme assay good
whole blood LTB
4
production inhibition was seen (IC
50
49 nM). This analog demonstrated excellent oral
bioavailability in the mouse ex vivo assay with an ED
90
in the 13 mg kg
1
range. The clinical backup was analog 97
(mouse ex vivo LTB
4
production ED
90
97% Inhibition at 3 mg kg
1
) which was selected based on a rhesus monkey
assay and showed excellent potency when dosed orally, inhibiting the production of LTB
4
with an ED
90
o10 mg kg
1
.
Unfortunately, these compounds failed preclinical safety studies due to the accumulation of a long-lived metabolite in
adipose tissue and mild hepatic toxicity.
260
To date, leukotriene modulation has been approached from several different avenues resulting in few marketed
products. Most clinical trials have focused and concluded for asthma and only recently has the trend shifted toward
other inammation targets.
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Biographies
Gregory P Roth, PhD, is currently Associate Director of Medicinal Chemistry at the Abbott Bioresearch Center
located in Worcester, MA. Greg obtained his doctorate degree in asymmetric synthesis under the supervision of Prof
Albert I Meyers at Colorado State University in 1988. Prior to joining Abbott Laboratories, Greg contributed to drug
discovery efforts at Bristol-Myers Squibb starting in 1988 and then joined Boehringer Ingelheim Pharmaceuticals in
1994 where he was involved in process research, combinatorial chemistry, and immunoscience-based drug discovery
programs.
David W Green, PhD, is Senior Associate Director of High Throughput Screening and Molecular Phamacology at
Amgen, Inc. in Cambridge, MA. He received his graduate training in mechanistic enzymology at the University of Iowa
with Prof Bryce V Plapp (PhD, 1988) and as a postdoctoral fellow in Monsanto Corporate Research. He joined
SmithKline Beecham in 1989 and contributed to anti-inammatory and antiviral drug discovery teams. David went on
to lead cardiovascular drug discovery programs at Bristol-Myers Squibb before managing enzymology and HTS groups
involved in structure-based drug design at 3-Dimensional and Cubist Pharmaceuticals. Before joining Amgen, he was
Associate Director of Molecular and Cellular Biology at Abbott Bioresearch Center where his responsibilities included
leading projects targeting cellular receptors for the development of anti-inammatory drugs.
& 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II
No part of this publication may be reproduced, stored in any retrieval system or transmitted
in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying,
recording or otherwise, without permission in writing from the publishers
ISBN (set): 0-08-044513-6
ISBN (Volume 7) 0-08-044520-9; pp. 873916
916 Asthma and Chronic Obstructive Pulmonary Disease