Design-driven LO: The discovery of new ultra long acting dibasic β2-adrenoceptor agonists

Article abstract of DOI:10.1016/j.bmcl.2011.05.097

Starting with the molecular scaffold of the DA₂/β ₂ dual agonist sibenadet (Viozan), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its

Full text of DOI:10.1016/j.bmcl.2011.05.097

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4612–4616
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design-driven LO: The discovery of new ultra long acting dibasic
b2-adrenoceptor agonists
Stephen Connolly a, , Lilian Alcaraz a, Andrew Bailey a, Elaine Cadogan b, Jadeen Christie a, Anthony R. Cook a,
⇑
Adrian J. Fisher a, Stephen Hill a, Alexander Humphries a, Anthony H. Ingall a, Zoe Kane d, Stuart Paine c,
Garry Pairaudeau a, Michael J. Stocks a, Alan Young b
a Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
b Department of BioScience, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
c Department of Drug Metabolism and Pharmacokinetics, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
d Department of Early Development, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Starting with the molecular scaffold of the DA2/b2 dual agonist sibenadet (Viozan™), a number of molec-
ular changes were incorporated, which were designed to increase the potency and selectivity of the target
molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full b2-agonist
with high selectivity and long duration capable of being dosed once daily has been discovered.
Ó 2011 Published by Elsevier Ltd.
Received 5 April 2011
Revised 24 May 2011
Accepted 25 May 2011
Available online 13 June 2011
Keywords:
LABA
b2-Agonist
Adrenoceptor agonist
Asthma
COPD
Inhaled
Duration
Inhaled b2-agonists have formed the mainstay of asthma and
COPD (chronic obstructive pulmonary disease) treatment for many
years.1 Treatment options were improved with the introduction of
second generation long-acting b2-agonists (LABA’s). In particular,
the inhaled combination of the long-acting b2-agonist formoterol
(1) with the steroid budesonide (Symbicort™) and the combina-
tion of the long-acting b2-agonist salmeterol (2) with the steroid
fluticasone (Seretide™) have provided enhanced benefit to patients
in recent years.2
However, both aforementioned clinically used combinations
contain LABA’s which have insufficient duration for once-daily
(uid) dosing, and need to be taken twice-daily (bid), which may
mean that they deliver a sub-optimal bronchodilation effect to
patients, while a bid dosing regime also introduces compliance
difficulties. It has been proposed that an inhaled ultra long acting
b2-agonist (uLABA), capable of bringing optimal 24-h bronchodila-
tion through a uid dosing regime, would be likely to improve patient
outcomes.3 Pharmaceutical companies have responded to this need
by designing such uid uLABA’s, and a variety of this work has
recently been published.4 Notably, the earliest of these uLABA’s,
indacaterol (3), has recently been accepted for registration in Eur-
ope.5 and more lately two further clinical candidates vilanterol
and olodaterol have also been described.6 We wish to describe some
of our own efforts in this area towards an inhaled uLABA, which has
high efficacy with full agonism, with a formoterol-like fast-acting
onset of action, the potential for a superior therapeutic index, and
uid duration. The latter was driven by ensuring a sufficiently long
terminal pharmacokinetic (PK) half-life in pre-clinical species and
was achieved by a combination of reducing clearance and increasing
distribution into lung tissue. Although ultimately targeted for lung
delivery by inhalation, the compounds were dosed intravenously
as in-house experience had shown that lung half-life correlated
with plasma half-life.7
Our group has previously described the dual DA2/b2-agonist sib-
enadet (4) (Viozan™).8 Since this compound had a safety profile
commensurate with reaching phase III clinical trials, it was decided
to use this scaffold as a starting point to search for a new ultra long
acting b2-agonist. To eliminate the DA2 activity of sibenadet the
ubiquitous chiral hydroxyl group, which was uniquely absent in
sibenadet, was re-installed, and it was hoped that this would also
ensure high agonist activity at the b2-receptor. In practise, intro-
duction of the hydroxyl group successfully gave compounds with
⇑
Corresponding author. Tel.: +44 1509 644160.
E-mail address: steve.connolly@astrazeneca.com (S. Connolly).
0960-894X/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2011.05.097

S. Connolly et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4612–4616
4613
excellent agonism, and reduced activity at the DA2 receptor to pro-
duce high selectivity (see Supplementary data). However, this tac-
tic also reduced b1 selectivity such that it had to be re-optimised in
this full agonist series. It is worth noting that initial b2:b1 selectiv-
ity was measured as b2 functional potency versus b1 binding po-
tency (as shown in Tables 1–3). As binding potency is always
greater than or equal to functional potency selectivity measured
in this way approximates to the minimum value, and could be
much higher if binding potency translates to reduced functional
potency. In reality, when selectivity was later measured as a ratio
of b2:b1 functional:functional potencies for selected compounds,
the receptor selectivities were indeed similar (see Supplementary
data). In addition, the chain sulphone group in sibenadet was re-
placed by a simple sulphide, thereby removing a major electron-
withdrawing effect on the basic chain amino-group. Indeed the
first molecule in this series, compound 5, showed extremely high
potency, and equivalent agonism to formoterol. However, this
compound, and the analogous compounds 6 and 7 with subtle
changes to the linking alkyl chain, all showed high rat hepatic turn-
over precluding in vivo PK testing. Compound 8 with a naphthyl
group terminating the chain also had excellent potency and agon-
ism, but, in spite of a somewhat lower rat hepatocyte turnover,
when measured in vivo it had a mediocre intravenous (iv) half-life
(3.6 h) as well as insufficient b1-receptor selectivity.
in the chain by NH gave a dibasic b-agonist, compound 11.
Pleasingly this compound retained good potency and high agon-
ism, and had low hepatic turnover. When dosed in vivo 11 had
an encouraging rat iv PK half-life of >10 h, and also displayed excel-
lent b1-selectivity.
Compound 11 met all our criteria for a uid LABA at this stage.
However, when tested in vivo in a guinea-pig model of duration
this compound narrowly failed to show activity at 24 h. Since this
guinea-pig model of duration showed excellent correlation with
the duration of known b2-agonists in man it was clear that this
dibasic series could be optimised by increasing duration further.
It was rationalised that the improved duration of dibasic
b2-agonists was due to the increased volume of distribution (Vss)
obtained by incorporation of a second amino-group, but that this
also had the effect of reducing the lipophilicity drastically (com-
pare 5 with 11), and so we reasoned that addition of lipophilic
groups on the terminal phenyl would further increase Vss and iv
half-life.
Addition of groups to the para-position (compounds 12 and 13)
reduced potency somewhat, and removed good b1-selectivity. A
meta-trifluoromethyl group (as in compound 14) was also bad
for b1-selectivity, but a meta-chloro substituent (as in compound
15) gave excellent potency and intrinsic activity, as well as in-
creased lipophilicity, and still retained excellent rat hepatocyte sta-
bility. When tested in vivo compound 15 did indeed have an
increased rat iv half-life, but at 34 h was, in fact, deemed too long.
On the other hand the corresponding ortho-chloro analogue 16
showed equivalent potency, intrinsic activity and b1-selectivity to
15, but, due to a slightly higher rat hepatocyte turnover, 16 showed
an intermediate rat iv half-life of almost 16 h, exactly as desired to
predict excellent uid duration in man.
To reduce the lipophilicity of compound 5, the sulphide was re-
placed by an ether link to give compound 9, and this had the desired
effect of reducing both lipophilicity and hepatic turnover. Disap-
pointingly, when this compound was measured in vivo the rat iv
PK half-life was rather short (1.4 h), and in this series inclusion of
naphthyl as in compound 10, only gave increased rat hepatic
turnover.
Since the hydroxyl benzothiazolone head group used as a
catechol mimic in this series is more acidic than the more usual
catechol mimic groups it was decided to incorporate a second basic
group in the molecule with a view to increasing the volume of dis-
tribution and increasing the half-life. Replacing the distal O-atom
Addition of a second chloro-atom gave the dichloro-analogue
17, which surprisingly retained good potency and agonism, but,
presumably due to its higher lipophilicity, had increased rat hepa-
tocyte turnover and a shorter rat iv PK half-life. Thus both unsub-
stituted phenyl and dichlorophenyl groups (compounds 11 and 17)
Table 1
Known b2-agonists
OH
H
OH
H
N
N
O
Me
HO
OMe
HO
HO
HN
H
O
(1)
(2)
OH
H
Et
Et
H
N
N
S
O
HO
O O
HO
S
HN
N
H
O
O
(3)
(4)
Compound
Name
b2 potencya (IAb) pEC50
log Dc
Rat Hepd
Duration
b1 binding (selectivity) pIC50 (ratio)
(1)
(2)
(3)
(4)
Formoterol
Salmeterol
Indacaterol
Sibenadet
9.0 (1.0)
9.1 (0.55)
7.8 (0.9)
9.2 (0.7)
0.4
1.9
2.7
2.6
76
85
51
>117
bid
bid
uid
<6.2 (>600)
6.3 (769)
6.5 (21)
<5 (>14,000)
a
Stimulation of cAMP accumulation in H292 cells expressing human b2, pEC50 is the negative logarithm of the molar drug concentration that produces a cAMP response
equal to 50% of its maximum.
b
IA is intrinsic activity measured as an agonist relative to formoterol (IA = 1).
c,d
Log D and rat hepatic turnover measured as described in Supplementary data.

4614
S. Connolly et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4612–4616
Table 2
b2-Agonists with extended side-chains akin to sibenadet
OH
H
(CH2)m
X
(CH2)n
Y
(CH2)2Ar
N
HO
S
N
H
O
Compound
m
X
n
Y
Ar
b2 potencya (IAb) pEC50
log Dc
Rat Hepd
iv PK t1/2 (h)
b1 binding (selectivity) pIC50 (ratio)
(4) sibenadet
(5)
(6)
(7)
(8)
(9)
(10)
(11)
2
2
3
3
3
3
3
2
SO2
S
S
S
S
O
O
S
3
3
2
3
2
2
2
3
O
O
O
O
O
O
O
NH
Ph
Ph
Ph
Ph
9.2 (0.7)
10.2 (1.0)
10.1 (1.0)
10.1 (0.9)
10.0 (1.0)
9.9 (0.9)
9.9 (1.0)
9.1 (0.9)
2.6
2.5
2.3
>2.5
3.1
1.1
2.3
0.1
>117
>150
>113
96
85
58
<5 (>14,000)
8.1 (136)
8.1 (108)
8.4 (47)
8.1 (76)
8.5 (27)
1-Naphthyl
Ph
1-Naphthyl
Ph
3.5
1.4
118
9
8.5 (27)
6.6 (307)
10.8
a
Stimulation of cAMP accumulation in H292 cells expressing human b2, pEC50 is the negative logarithm of the molar drug concentration that produces a cAMP response
equal to 50% of its maximum.
b
IA is intrinsic activity measured as an agonist relative to formoterol (IA = 1).
c,d
Log D and rat hepatic turnover measured as described in Supplementary data.
Table 3
b2-Agonists incorporating a second basic centre
OH
H
(CH2)m
X
(CH2)n
Y
(CH2)2Ar
N
HO
S
N
H
O
Compound
m
X
n
Y
Ar
Ph
b2 potencya (IAb) pEC50
log Dc
Rat Hepd
9
iv PK t1/2 (h)
b1 binding (selectivity) pIC50 (ratio)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
S
S
S
S
S
S
S
SO
SO2
O
S
S
S
O
O
O
3
3
3
3
3
3
3
3
3
3
2
2
2
2
2
2
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NMe
9.1 (0.9)
8.4 (0.9)
7.9 (0.7)
8.5 (0.8)
9.0 (0.8)
9.2 (0.8)
8.8 (0.9)
8.3 (0.8)
9.2 (1.0)
9.3 (1.0)
8.9 (1.1)
9.4 (0.8)
8.8 (1.0)
9.7 (1.0)
9.1 (0.9)
8.6 (0.9)
0.1
0.9
0.4
1.2
1.0
1.0
2.2
0.2
10.8
6.6 (307)
7.3 (11)
6.9 (11)
7.0 (32)
6.8 (183)
6.9 (187)
7.1 (62)
6.8 (26)
6.1 (1259)
7.0 (178)
6.9 (89)
7.4 (100)
7.1 (45)
7.2 (45)
7.3 (63)
6.4 (150)
4-Et Ph
4-OEt Ph
3-CF3 Ph
3-Cl Ph
2-Cl Ph
2,3-diCl Ph
3-Cl Ph
3-Cl Ph
3-Cl Ph
3-Cl Ph
2-Cl Ph
2,3-diCl Ph
3-Cl Ph
2,3-diCl Ph
Ph
8
6
7
11
19
7
33.7
15.9
10.1
0.8
1.1
1.0
1.7
0.0
0.6
12
<3
10
a
Stimulation of cAMP accumulation in H292 cells expressing human b2, pEC50 is the negative logarithm of the molar drug concentration that produces a cAMP response
equal to 50% of its maximum.
b
IA is intrinsic activity measured as an agonist relative to formoterol (IA = 1).
c,d
Log D and rat hepatic turnover measured as described in Supplementary data.
have shorter iv PK half-lives than the intermediate monochloro
compound 16. This is likely due to opposing effects on volume of
distribution and clearance.
a similar reduction in b1-selectivity is also observed by incorpora-
tion of an O-atom one atom further along the chain (compare 24
and 25 with 15 and 17). Finally, methylating the linking second
base N-atom, as in 26, reduced both potency and b1-selectivity.
From this series compound 16 appeared to have the optimal
profile, and was chosen for further evaluation.
With monochloro phenyl substitution appearing optimal we
next examined other effects in the linking chain. Replacement of
the S atom with SO or SO2 reduced lipophilicity (compounds 18
and 19). However, incorporation of a sulphoxide group reduces
b2-potency such that b1-selectivity is eroded. In contrast sulphone
19 has excellent b2-potency and reduced b1-activity giving it the
best selectivity in this series, however its very low lipophilicity
made it unattractive, and this compound was not progressed.
Replacement of the S-atom with an O-link gave compound 20,
whose profile was very similar to compound 16.
OH
H
N
S
N
H
Cl
HO
S
N
H
O
16
Moving the S-link along the chain by one atom to give an anal-
ogous series as in compounds 21–23 gave compounds with similar
profile to compounds 15–17 but with reduced b1-selectivity, while
The synthetic sequence for compound 16 is shown below to
illustrate the process for all analogues.9

S. Connolly et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4612–4616
4615
O
O
O
O
O
O
H
3.
2.
1.
H2N
N
S
N
S
N
HO
O
Cl
Cl
Cl
Cl
Scheme 1. Reagents: (1) (a) Boc2O, Et3N, 100%; (b) NaH, allyl bromide, 64%; (2) 2-mercaptoethanol, AIBN, 81%; (3) sulphur trioxide–pyridine complex, 52%.
O
O
O
O
OH
S
O
3.
S
4.
S
O
S
O
1.
2.
HN
HN
HN
HN
N3
Cl
N3
HO
HO
HO
HO
O
2.HBr
S
O
O
6.
S
OH
5.
H
N
S
OH
S
OH
HN
H
N
N
H
HN
HN
HO
NH2
S
N
boc
Cl
HO
Cl
HO
(17)
Key chiral
intermediate
Scheme 2. Reagents: (1) chlorination, 95%; (2) NaN3 88%; (3) B2H6, Corey’s reagent, 99%, 96% enantiomeric purity; (4) H2, Pd–C, 64%; (5) NaCNBH3, AcOH 42%; (6) (a) TFA,
CH2Cl2 (b) aqueous HBr, 58% for two steps.
The aldehydes necessary for coupling were prepared by Boc-pro-
tection of the appropriatephenethylamine and subsequent N-allyla-
tion. This was followed by radical addition of 2-mercaptoethanol,
and finally oxidation by Dess–Martin reagent (see Scheme 1).
The known acetyl benzothiazolone,10 used in the large-scale syn-
thesis of sibenadet, was available to us in large quantities. This
material was selectively chlorinated on the acetyl group, and the
chloro-group replaced by azide. At this stage an enantiospecific
reduction, using Corey reagent,11 successfully installed the required
chiral alcohol group, and the azide was reduced to give the key chi-
ral amino-alcohol used to prepare all compounds in this series.
The aldehyde and chiral amino-alcohol were coupled by reduc-
tive amination. The Boc-group was removed with trifluoroacetic
acid, and the free base was converted to the crystalline dihydrobr-
omide salt with aqueous hydrobromic acid (see Scheme 2).
Figure 1. Duration of action of compound 16 versus standards (dosed i.t.).
Compounds which demonstrated required potency and agon-
ism, and had convincing stability against rat hepatocyte turnover
were measured for plasma half-life in rat. Later measurements of
lung concentration confirmed this equivalence of half-life in lung.
When dosed iv in rat compounds 11 and 15–17 all showed long
plasma half-lives, and when dosed intra-tracheally (i.t.) the lung
half-life’s were essentially identical. Compound 16 with a 15.9 h
rat plasma half-life was selected for testing in a guinea-pig model
of bronchoconstriction.
Inhaled b-agonists could have systemic side effects from the
swallowed fraction. However, as expected from a phenol, when
tested orally 16 had extremely low bioavailability (<1%) precluding
any systemic activity via the oral route.
Histamine-induced bronchoconstriction in guinea-pig is a well
characterised model of human lung disease,12 and bronchodilators
offering protection in this model have historically shown good
efficacy in man. Compound 16 was first tested at various concentra-
tions dosed by intra-tracheal instillation (i.t.) to establish a dose–
response for protection against histamine-induced bronchocon-
striction. In this model 16 had an ED80 of 7 lg/kg. To measure the
duration of the bronchoprotective effect in vivo 16 was then dosed
intra-tracheally at its measured ED80, and the remaining level of
bronchoprotection measured at various time points over the next
24 h. To compare compounds fairly all compounds were dosed at
their ED80 value, this concentration being measured in a separate
full dose–response curve for each compound. This level of inhibition
was reproduced in the duration experiment as clearly shown by the
inhibition measured for each compound at the initial time point.
Therefore duration is measured as maintenance of inhibition from
an equivalent level at the initial time point. By measuring the bron-
choprotection remaining, and comparing this with standard bid
compounds salmeterol and formoterol it was judged that >40%
bronchodilation should remain at 24 h to predict an inhaled 24-h
bronchodilator effect in man. As shown in Figure 1 compound 16
showed 49% inhibition at 24 h, very similar to indacaterol.

4616
S. Connolly et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4612–4616
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have good solid state properties to allow for micronisation. A salt
screen was performed, and it was found that the di-hydrobromide
salt of compound 16 showed excellent crystallinity, a high melting
point and no hygroscopicity. This salt was subsequently shown to
micronise to particles <5
inhaled properties.
lm without issue, and have acceptable
Starting with the dual DA2/b2-agonist sibenadet structure we
have designed new inhaled ultra long acting b2-agonists (uLABA’s).
Firstly, addition of a benzylic hydroxyl group improved potency,
intrinsic activity and selectivity against the dopamine receptor.
Secondly, incorporation of a second base along the chain increased
Vss and rat plasma PK half-life. Half-life in the dibasic series was
then optimised by adjusting lipophilicity to an appropriate level
until the desired plasma half-life was achieved in rat. This long
rat plasma half-life translated well into rat lung half-life, and also
to guinea-pig duration of bronchoprotection, as well as predicting
an appropriately long half-life in man. In summary, compound 16
met all our criteria, and the dihyrobromide salt of this compound
was selected to progress into development.
5. Indacaterol was launched in Germany in September 2009, and in Denmark and
Ireland in March 2010, Novartis Press Releases.
6. Synthesis and structure–activity relationships of long-acting b2 adrenergic
receptor agonists incorporating metabolic inactivation: An antedrug approach:
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.05.097.
7. Paine, S., manuscript in preparation.
8. Bonnert, R. V.; Brown, R. C.; Chapman, D.; Cheshire, D. R.; Dixon, J.; Ince, F.;
Kinchin, E. C.; Lyons, A. J.; Davis, A. M.; Hallam, C.; Harper, S. T.; Unitt, J. F.;
Dougall, I. G.; Jackson, D. M.; McKechnie, K.; Young, A.; Simpson, W. T. J. Med.
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9. Syntheses of compounds in this Letter are described more fully in
WO2007027134.
10. Synthesis of the key intermediate is described in WO2009098448.
11. (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 3431; (b) Mathre, D. J.;
Jones, T. K.; Xavier, L. C.; Blacklock, T. J.; Reamer, R. A.; Mohan, J. J.; Turner
Jones, E. T.; Hoogsteen, K.; Baum, M. W.; Grabowski, E. J. J. Org. Chem. 1991, 56,
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References and notes
1. (a) Waldeck, B. Eur. J. Pharmacol. 2002, 445, 1; (b) Siafakas, N. M.; Vermeire, P.;
Price, N. B. Eur. Respir. J. 1995, 8, 1398.
2. (a) Johnson, M. Med. Res. Rev. 1995, 15, 225; (b) Anderson, G. P. Life Sci. 1993, 52,
2145; (c) Palmqvist, M.; Persson, G.; Lazer, L.; Rosenborg, J.; Larsson, P.; Lotvall,
J. Eur. Respir. J. 1997, 10, 2484; (d) Matthys, H. Respiration 2001, 68, 432.
3. Cazzola, M.; Segreti, A.; Matera, M. G. Curr. Opin. Pulm. Med. 2010, 16, 6.
4. Much work has recently been published concerning efforts to design other
uLABA’s (a) Brown, A. D.; Bunnage, M. E.; Glossop, P. A.; James, K.; Jones, R.;
Lane, C. A. L.; Lewthwaite, R. A.; Mantell, S.; Perros-Huguet, C.; Price, D. A.;
12. Walland, A.; Palluk, R.; Burkard, S.; Hammer, R. Eur. J. Pharmacol. 1997, 330, 213.