Molecular hybridization yields triazole bronchodilators for the treatment of COPD

Article abstract of DOI:10.1016/j.bmcl.2015.10.008

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a β₂ agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.

Full text of DOI:10.1016/j.bmcl.2015.10.008

Bioorganic & Medicinal Chemistry Letters 25 (2015) 5121–5126
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular hybridization yields triazole bronchodilators for the
treatment of COPD
b
b
c
c
d
Lyn H. Jones a, , Jane Burrows , Neil Feeder , Paul Glossop , Kim James , Rhys M. Jones ,
Amy S. Kenyon c, Sheena Patel e,f, Dannielle F. Roberts c, Matthew D. Selby c, Ross S. Strang c,
Emilio F. Stuart e, Michael A. Trevethick e, Jessica Watson e, Karen N. Wright e, Nick Clarke e,g
⇑
a WorldWide Medicinal Chemistry, 610 Main Street, Cambridge, MA 02139, USA
b Pharmaceutical Sciences, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK
c WorldWide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK
d Pharmacokinetics, Dynamics and Metabolism, 610 Main Street, Cambridge, MA 02139, USA
e Allergy and Respiratory Biology, Pfizer, Ramsgate Road, Sandwich CT13 9NJ, UK
f CVMED Research Unit, Pfizer, Cambridge, MA 02139, USA
g Inflammation and Immunology Research Unit, Pfizer, 610 Main Street, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic
antagonists, and subsequent integrative conjugation to a b2 agonist quinolinone furnished a new class
of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles
of ‘inhalation by design’ furnished a clinical candidate with desirable pharmacological, pharmacokinetic
and biopharmaceutical properties.
Received 1 August 2015
Revised 29 September 2015
Accepted 5 October 2015
Available online 8 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
MABA
Inhalation by design
COPD
Bronchodilator
Bifunctional
Chronic obstructive pulmonary disease (COPD) is a leading
cause of morbidity and mortality worldwide, and the chronic
inflammation associated with the disease leads to emphysema
and bronchiolitis.1 Long-acting b2-adrenoceptor agonists (LABAs)
and long-acting muscarinic receptor antagonists (LAMAs) form
the basis of existing bronchodilator pharmacological treatment.2
It has also been shown that bifunctional agents that possess dual
pharmacology muscarinic antagonist and b2 agonist properties
(so-called MABAs) can achieve greater efficacy than single bron-
chodilator modalities alone.3 Triple therapy for COPD, consisting
of an anti-inflammatory inhaled corticosteroid (ICS) combined
with a LABA and LAMA, will likely provide optimal therapeutic effi-
cacy, particularly for those with concomitant asthma, and an
opportunity to address the flare associated with exacerbations.1,4,5
However, there are significant technical hurdles to combine three
separate drugs in a single inhaler, and therefore the combination
of two drugs, a MABA and an ICS would provide substantially
simpler opportunities for triple therapy.6,7
We, and others, have described the design and development of
dual pharmacology MABAs for the treatment of COPD, with a view
to their eventual combination with ICS agents to enable the triple
therapy concept (see for example those from Theravance and Pfizer
in Figure 1).8–11 Here we present the design of a 1,2,4-triazole mus-
carinic antagonist template which enabled the creation of novel
bifunctional MABAs, culminating in the development of a clinical
candidate.
A detailed description of the design of the triazole-contain-
ing muscarinic antagonist series will appear elsewhere. Briefly,
an investigation into novel heterocyclic replacements of the
ester linkages often seen in antimuscarinic templates, such as
ipratropium, tiotropium and enpiperate,12 provided the 1,2,
4-triazole isostere as an effective mimic that retained the
desired pharmacology (Fig. 2 and Table 1—in fact, triazole 1
was more potent than the parent ester enpiperate).13 The
syntheses of all triazole muscarinic antagonists and MABAs in
this manuscript were described previously.14 Other groups
have also reported alternative heterocyclic replacements
in the development of novel antimuscarinic agents and
MABAs.8,9
⇑
Corresponding author. Tel.: +1 617 665 5631.
E-mail address: lyn.jones@pfizer.com (L.H. Jones).
http://dx.doi.org/10.1016/j.bmcl.2015.10.008
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.

5122
L. H. Jones et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5121–5126
OH
cell-based activity, the kinetics of pharmacological duration
H
N
OH
against the M3 receptor (using tritiated N-methyl scopolamine in
a dilution-based methodology described previously)19,20 were rel-
atively poor. Additionally, the metabolic stability of 3 was rather
high (as assessed in human liver microsomes, HLM) and there
was no evidence of glucuronidation (assessed in HLM in the
absence of NADPH and the presence of microsomal activator Brij58
and UDPGA).21 The polarity of the triazole ring imparts higher
hydrophilicity to the resulting conjugate, which likely drives these
observations (cf. cLogP of PF-04268168 and PF-04348235 to 3,
Table 1).
The benzene-diethylamine linker was also used to conjugate
the b2 and M3 head groups (precedence exists for this linker in
biaryl carbamate MABAs)8 to furnish 4. Unfortunately, this modifi-
cation had a detrimental effect on the primary pharmacology,
although surprisingly, the HLM turnover was higher, even though
the molecule was more polar than 3.
The cyclohexyl-containing triazole MABA 5 was prepared as an
epimeric mixture to ascertain the effect of saturating one of the
benzene rings in the antimuscarinic pharmacophore.14 The result-
ing increase in lipophilicity likely caused the higher metabolic
turnover, and adequate primary pharmacology for both b2 and
M3 components was attained. As a result of these preliminary
results, the racemic precursor was resolved to enable preparation
of the single active enantiomer, and subsequent conjugation
yielded 6 and 7. Both MABAs possessed good primary pharmacol-
ogy, kinetics and high metabolic turnover in HLM (Table 1). Inter-
estingly, the benzene-diethylamino-linked MABA 7 demonstrated
higher glucuronidation than 6, and therefore this congener
(PF-04810097) was chosen for further in vivo and ex vivo
profiling. The simultaneous optimization of dual pharmacology
and phase I plus II metabolism is a feature of our medicinal
chemistry program that differentiates this work from previous
MABA drug discovery.11
N
O
HO
HN
PF-04268168
O
H
N
O
OH
H
O
N
N
HO
OH
THRX-198321
PF-04348235
HN
Cl
O
H
N
O
OH
H
N
O
N
HO
HN
HN
SO2Me
OH
H
N
N
O
O
HO
O
N
H
THRX-200495
O
O
Cl
H
N
N
N
OH
O
H
O
N
O
N
H
As found for many other antimuscarinic templates, PF-
04810097 exhibited non-selective muscarinic receptor antagonist
activity (Ki M1, M2, M3, M4, M5 = 0.16, 0.14, 0.29, 0.35, 1.1 nM,
respectively). The M3 off rate of PF-04810097 was relatively
slower than ipratropium (T1/2 <15 min) but significantly faster than
OMe
TD-5959
HO
HN
O
Figure 1. Known dual pharmacology MABA bronchodilators from Pfizer (PF-
04268168 and PF-04348235) and Theravance (THRX-196321, THRX-200495 and
TD-5959).
tiotropium (>1372 min) (we had previously shown that
a
cLogP >5.5 for MABAs was required for long offset kinetics).19
We also observed a mismatch between M3 offset kinetics and
antimuscarinic duration of action in the ex vivo guinea pig trachea
(GPT) assay in another MABA series,16 and we were therefore keen
to explore the GPT efficacy and duration of PF-04810097 (Table 2).
PF-04810097 produced a concentration-related and potent
inhibition of the GPT contraction induced by electric field stimula-
tion, which captures both b2 and M3 axes. The b2 antagonist pro-
pranolol was then used to delineate the M3 component of
bronchodilation, and PF-04810097 retained excellent potency.
The duration of action (DoA—the time taken for the EFS response
to recover by 25% of the inhibition induced, T25%) was impressive,
both in the presence and absence of propranolol. The apparent
mismatch with the M3 offset kinetics suggests an alternative
mechanism at play in the tissue assay, although further work is
warranted to fully explain these observations (a similar effect
was reported recently for another MABA11). PF-04810097 was also
a potent inhibitor of histamine induced contractions of the isolated
GPT preparation (Table 2), which is indicative of b2 efficacy only, as
previously described.19
Piperidine was chosen as the motif bearing the key antimus-
carinic pharmacophoric nitrogen as it appeared in many MABA
templates previously and our own analysis showed that more syn-
thetically complex replacements provided no significant improve-
ments in potency, at least in the biaryl carbamate series.15
Saturation of one of the benzene rings to a cyclohexane had been
shown to improve the potency of other antimuscarinic series,16,17
and although there appeared to be little affect in the case of race-
mic triazole 2 (Fig. 2 and Table 1), we decided that the commensu-
rate increase in lipophilicity of this transformation may positively
modulate the pharmacodynamics and pharmacokinetics of a MABA
containing this motif (see below).
Next, we conjugated the triazole antimuscarinic motifs to the
precedented quinolinone b2 agonist head group to create novel
MABAs. The quinolinone agonist trigger was chosen due to its
use in several MABA series previously (THRX-198321 for example),
and its propensity for glucuronidative phase II metabolism via phe-
nol glycosylation, that can mitigate potential issues for drug-drug
interactions (DDIs).15 We initially chose the C9-linker to conjugate
the b2 and M3 motifs (due to the potential multivalent effects of
the resultant MABA18 and from precedence in our own work)16
to yield 3 (Table 1). Although 3 possessed adequate b2 and M3
PF-04810097 was also assessed for its ability to inhibit
methacholine-induced bronchoconstriction in the conscious dog
model via intratracheal administration in a micelle solution.
PF-04810097 was
a potent and long lasting inhibitor of
bronchoconstriction in the dog (the potency for PF-04810097
was comparable to other agents such as ipratropium and

L. H. Jones et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5121–5126
5123
S
OH
O
O
OH
+
Br-
+
O
O
Br-
S
N
N
O
tiotropium bromide
ipratropium bromide
N
OH
N
OH
O
OH
N
N
N
N
N
O
N
N
2
1
enpiperate
Figure 2. Derivation of 1,2,4-triazole template from the ester-containing antimuscarinics (exemplified by enpiperate). Manual overlay of energy-minimized structures of
enpiperate (green) and triazole 1 (magenta) illustrating colocalization of hydrogen bonding groups, benzene rings and the basic nitrogen atoms.
Table 1
In vitro pharmacological and metabolic profiles of PF-04268168, PF-04348235, enpiperate and 1,2,4-triazolesa
M3 offsetc
(min)
HLMd
l/min/mg)
Glucuronidatione
l/min/mg)
cLogP
b
Compound
b2 EC50
(nM)
b2 fold
M3 Ki
(nM)
shiftb
(
l
(l
OH
H
N
OH
N
2.4
1.1
0.31
>1200
74
<3
6.6
HO
HN
O
PF-04268168
O
OH
Cl
H
O
N
OH
H
N
3.7
1.5
0.73
117
23
24
5.3
O
N
HO
HN
PF-04348235
enpiperate
O
OH
n/a
n/a
n/a
n/a
1.1
nd
nd
nd
nd
nd
nd
2.5
1.2
O
O
N
N
N
OH
0.34
N
N
N
1
N
N
OH
n/a
n/a
1.1
nd
nd
nd
2.8
N
2
(continued on next page)

5124
L. H. Jones et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5121–5126
Table 1 (continued)
b
Compound
b2 EC50
(nM)
b2 fold
M3 Ki
(nM)
M3 offsetc
(min)
HLMd
l/min/mg)
Glucuronidatione
l/min/mg)
cLogP
shiftb
(
l
(l
N
OH
N
OH
H
N
N
N
13
3.5
6.4
1.5
3.7
<15
18
<3
<3
3.2
3.7
HO
HN
3, PF-04381338
O
OH
H
N
N
HO
HN
N
116
18
nd
47
2.6
4.8
OH
N
N
O
4, PF-04543253
N
OH
N
OH
H
N
N
N
21
7.7
491
160
HO
HN
5, PF-04336022
O
N
OH
N
OH
H
N
N
N
14
1.2
2.1
3.7
278
133
130
4
9
4.8
3.7
HO
HN
6, PF-04631143
O
OH
H
N
N
HO
HN
N
20.9
0.29
<100
OH
N
N
O
7, PF-04810097
a
nd = not determined; n/a = not applicable.
b
c
Washed and unwashed agonist potency of compounds at the b2 adrenoceptor, by measuring their ability to stimulate intracellular cAMP production in CHO-h b2 cells.
offset kinetics from human cloned M3 receptor using [3H] N-methyl scopolamine (dilution method).
Clearance values in human liver microsomes.
Glucuronidation rate assessed in HLM (ÀNADPH, +Brij, +UDPGA).
d
e
Table 2
Ex vivo and in vivo pharmacological profiles of lead triazole MABA PF-04810097, salmeterol and ipratropiuma
PF-04810097
Salmeterol
Ipra-tropium
b
GPT EFS EC50 (nM)
11.5
>16
10.2
>12.4
12.9
56
6.9
8.2
NA
NA
2.7
14
1.2
2.6
NA
NA
NA
11
No effect
<4
b
GPT EFS duration T25% (h)
c
GPT EFS + propranolol EC50 (nM)
GPT EFS + propranolol durationc (h)
d
GPT histamine EC50 (nM)
e
Conscious dog ID50
(
lg)
Conscious dog CV TIf
20-fold
16
7-fold
10
Conscious dog durationg (h)
a
All data are geometric means with 95% CI, at least n = 4.
GPT = Guinea pig trachea. EFS = Electric field stimulation. Potency and duration for b2 and M3 components of bronchodilation. Submaximal concentration used for the
b
duration is that which gives 70% inhibition of the EFS response.
c
Potency and duration for M3 component of bronchodilation.
Potency for b2 component of bronchodilation.
Bronchodilator effect in methacholine-induced bronchoconstriction model in conscious dogs.
Therapeutic index over heart rate and contractility in the methacholine-induced bronchoconstriction model in conscious dogs.
d
e
f
g
Duration of action in the methacholine-induced bronchoconstriction model in conscious dogs at 30 lg dose.

L. H. Jones et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5121–5126
5125
OH
H
N
N
HO
N
OH
HN
N
N
SO3H
O
.
.
H2O
SO3H
Figure 3. Scanning electron micrograph of freshly micronized PF-04810097 naphthalene 1,5-disulfonate hydrate showing very fine particles, typically less than 2 lm in
diameter.
O
1.2eq N2H4.H2O, AcOH,
PhMe, 90ºC, 2hrs
1eq CDI, PhMe,
ammonia, RT,
24hrs
O
O
PhMe, DMF-DMA,
90ºC, 2hrs
O
i) 0.5eq D-tyrosine methyl ester
MeCN, water, 80ºC to RT, 24hrs
N
N
H2N
HO
OH
HO
OH
OH
OH
taken on crude
89% over 2 steps
90-95%
ii) HCl
45 %
O
1eq
N
Boc
N
1eq
Br
O
Boc
N
N
Br
N
N
N
2eq Cs2CO3,
Acetone (20ml/g),
70ºC, 5hrs
HN
4M HCl/dioxane(2.7ml/g),
dioxane (5.5ml/g),
RT, 24hrs
OH
OH
OH
N
HN
N
3eq iPr2NEt, MEK (20ml/g),
90ºC, 24hrs
N
N
64%
52% over 2 steps
TBS
O
O
Br
1eq
N
H2N
10eq N2H4.H2O,
BnO
EtOH (12ml/g), RT, 1hr
O
N
N
N
N
HN
3eq NaHCO3,
OH
OH
90%
N
N
MeCN (30ml/g), 90ºC, 72hrs
O
N
N
31%
TBS
TBS
O
O
H
H
N
N
0.4eqPd(OH)2, 5eq NH4.HCO2,
EtOH (36ml/g), 78ºC,2hrs
N
N
HO
N
BnO
N
OH
OH
HN
HN
N
N
N
N
95%
O
O
5eq NH4F, MeOH
(21ml/g), 40ºC, 24h
78%
OH
H
OH
H
N
N
1eq napadisylic acid
SO3H
MeOH, H2O, 70ºC, 63h
N
N
HO
N
N
HO
70%
OH
OH
HN
HN
N
N
N
N
O
O
SO3H
PF-04810097
Figure 4. The discovery synthetic route to PF-04810097.
salmeterol in the same model (ID50 11 and 14
l
g respectively,
desired (concentrations were below the lower limit of detection)
thus minimizing potential risks from systemic exposure. The routes
of metabolism were determined in HLM and preclinical species (rat
and dog), which were consistent with N-dealkylation at the piper-
idine and secondary amine groups, and a glucuronide conjugate
of the b2 phenol was isolated in human hepatocytes as predicted.
Although further work is required to fully profile the pharmacology
of these metabolites, their very low predicted circulating levels, due
to inhaled dosing and poor oral bioavailability of the parent, miti-
gate potential issues arising from active metabolites.
Table 2). PF-04810097 also displayed a three-fold superior thera-
peutic index for heart rate and contractility over salmeterol in this
model. In anaesthetized rabbits, PF-04810097 did not cause activa-
tion of Ad fibers from the tracheobronchial tree, suggesting that it
would be unlikely to cause cough in humans following inhaled
administration.22 Also from a safety perspective, PF-04810097
was found to be clean in genetic toxicity screening (AMES and
in vitro micronucleus).
PF-04810097 exhibited a moderate plasma clearance (22 and
11 mL/min/Kg in rat and dog respectively) and a short-to-moderate
half life (1.7 and 4 h). Following oral solution administration to rats
(2 mg/Kg), bioavailability was determined to be low (<5%) as
A desirable solid form for inhalation dosing in a dry powder
inhaler (DPI) is extremely important in the development of a viable
bronchodilator, especially if the ultimate aim for a MABA is to

5126
L. H. Jones et al. / Bioorg. Med. Chem. Lett. 25 (2015) 5121–5126
combine it with an ICS. As other related MABAs had been crystal-
lized previously as their naphthalene 1,5-disulfonate salts using
Armstrong’s acid,15 this was also attempted with PF-04810097.
Pleasingly, PF-04810097 was crystallized as the naphthalene
1,5-disulfonate (melting point 257 °C), so enabling further devel-
opment (Fig. 3). From dynamic vapor sorption and thermal analysis
data, the solid form appeared to be hydrated and the crystal did not
change form upon dehydration and subsequent re-hydration.
Crystalline feed material was micronized at an air jet mill pressure
of 5 bar (in a MCOneÒ spiral jet mill) and the appearance of the
micronized particles did not change following two weeks exposure
to 75% relative humidity at 40 °C (Fig. 3). Jet milled material was
blended (1% w/w) with lactose (a common carrier excipient used
in DPIs) and accelerated stability testing at 70 °C, 75% relative
humidity for one week showed that no single impurity increased
to beyond the 0.3% level. The efficacious dose projection of
PF-04810097 naphthalene 1,5-disulfonate hydrate (based on
comparative data for the clinical agents salmeterol and iprat-
References and notes
1. Vestbo, J.; Hurd, S. S.; Agusti, A. G.; Jones, P. W.; Vogelmeier, C.; Anzueto, A.;
Barnes, P. J.; Fabbri, L. M.; Martinez, F. J.; Nishimura, M.; Stockley, R. A.; Sin, D.
D.; Rodriguez-Roisin, R. Am. J. Respir. Crit. Care Med. 2013, 187, 347.
2. Montuschi, P.; Ciabattoni, G. J. Med. Chem. 2015, 58, 4131.
3. Cazzola, M.; Lopez-Campos, J. L.; Puente-Maestu, L. Eur. Respir. J. 2013, 42, 885.
4. Welte, T.; Miravitlles, M.; Hernandez, P.; Eriksson, G.; Peterson, S.; Polanowski,
T.; Kessler, R. Am. J. Respir. Crit. Care Med. 2009, 180, 741.
5. Singh, D.; Brooks, J.; Hagan, G.; Cahn, A.; O’Connor, B. J. Thorax 2008, 63, 592.
6. Fuso, L.; Mores, N.; Valente, S.; Malerba, M.; Montuschi, P. Curr. Med. Chem.
2013, 20, 1477.
7. Montuschi, P.; Macagno, F.; Valente, S.; Fuso, L. Curr. Med. Chem. 2013, 20,
1464.
8. Hughes, A. D.; Jones, L. H. Future Med. Chem. 2011, 3, 1585.
9. Hughes, A. D.; McNamara, A.; Steinfeld, T. Prog. Med. Chem. 2012, 51, 71.
10. McNamara, A.; Steinfeld, T.; Pulido-Rios, M. T.; Stangeland, E.; Hegde, S. S.;
Mammen, M.; Martin, W. J. Pulm. Pharmacol. Ther. 2012, 25, 357.
11. Hughes, A. D.; Chen, Y.; Hegde, S. S.; Jasper, J. R.; Jaw-Tsai, S.; Lee, T. W.;
McNamara, A.; Pulido-Rios, M. T.; Steinfeld, T.; Mammen, M. J. Med. Chem.
2015, 58, 2609.
12. Xu, R.; Sim, M.-K.; Go, M.-L. Eur. J. Pharm. Sci. 1999, 8, 39.
13. Yang, R.-S.; Hu, G.-Q.; Huang, W.-L. Huaxue Shiji 2008, 30, 8.
14. Jones, L. H.; Roberts, D. F.; Strang, R. S. 2010; Vol. WO2010004517.
15. Hilton, L.; Osborne, R.; Kenyon, A. S.; Baldock, H.; Bunnage, M. E.; Burrows, J.;
Clarke, N.; Coghlan, M.; Entwistle, D.; Fairman, D.; Feeder, N.; James, K.; Jones,
R. M.; Laouar, N.; Lunn, G.; Marshall, S.; Newman, S. D.; Patel, S.; Selby, M. D.;
Spence, F.; Stuart, E. F.; Summerhill, S.; Trevethick, M. A.; Wright, K. N.; Yeadon,
M.; Price, D. A.; Jones, L. H. Med. Chem. Commun. 2011, 2, 870.
16. Osborne, R.; Clarke, N.; Glossop, P.; Kenyon, A. S.; Liu, H.; Patel, S.; Summerhill,
S.; Jones, L. H. J. Med. Chem. 2011, 54, 6998.
17. Carter, J. P.; Noronha-Blob, L.; Audia, V. H.; Dupont, A. C.; McPherson, D. W.;
Natalie, K. J., Jr.; Rzeszotarski, W. J.; Spagnuolo, C. J.; Waid, P. P.; Kaiser, C. J.
Med. Chem. 1991, 34, 3065.
18. Steinfeld, T.; Hughes, A. D.; Klein, U.; Smith, J.; Mammen, M. Mol. Pharmacol.
2011, 79, 389.
19. Jones, L. H.; Baldock, H.; Bunnage, M. E.; Burrows, J.; Clarke, N.; Coghlan, M.;
Entwistle, D.; Fairman, D.; Feeder, N.; Fulton, C.; Hilton, L.; James, K.; Jones, R.
M.; Kenyon, A. S.; Marshall, S.; Newman, S. D.; Osborne, R.; Patel, S.; Selby, M.
D.; Stuart, E. F.; Trevethick, M. A.; Wright, K. N.; Price, D. A. Bioorg. Med. Chem.
Lett. 2011, 21, 2759.
ropium in the well-studied conscious dog model) is 100–300
bid, 400–1000 g qd nominal dose, corresponding to a lung dose
of ꢀ20–60 g bid or ꢀ80–200 g qd, assuming 20% aerosolisation
lg
l
l
l
efficiency from the inhaler device. PF-04810097 was therefore
nominated as a clinical candidate for the treatment of COPD.
In conclusion, the 1,2,4-triazole motif was employed as a bioi-
sostere for the ester commonly used in muscarinic antagonists,
and subsequent conjugation to a b2 agonist quinolinone furnished
a new class of bifunctional MABAs. Further elaboration and devel-
opment of this series, including a detailed description of the phar-
macology and pharmacokinetics of PF-04810097, and its optimized
synthetic route (based on the discovery route described in Fig. 4) to
provide kilogram quantities of material, will appear elsewhere.
20. Watson, J.; Strawbridge, M.; Brown, R.; Campany, K.; Coghlan, M.; Trevethick,
M. A. Fund. Clin. Pharm. 2008, 22, 69.
Acknowledgement
21. Trubetskoy, O.; Finel, M.; Trubetskoy, V. J. Pharm. Pharmacol. 2008, 60, 1061.
22. Sladen, L.; Clarke, N.; Perros-Huguet, C.; Yeadon, M. Am. J. Respir. Crit. Care Med.
2011, 183, A3099 (poster).
We thank Kevin Dack, Alan Stobie and Mark Bunnage for useful
discussions.