An efficient asymmetric synthesis of the potent β-blocker ICI-118,551 allows the determination of enantiomer dependency on biological activity

Article abstract of DOI:10.1039/c0cc00142b

A highly efficient, practical and flexible two-step asymmetric synthesis of the β₂-selective β-blocker ICI 118,551 is reported, allowing an unambiguous determination of the dependency of biological activity with optical activity, revealing the S,S-enantiomer to be the most potent.

Full text of DOI:10.1039/c0cc00142b

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An efficient asymmetric synthesis of the potent b-blocker ICI-118,551
allows the determination of enantiomer dependency on biological
activitywz
James R. Baker,*a J. Daniel Hothersall,b Richard J. Fitzmaurice,a Matthew Tucknott,a
Andy Vinter,a Andrew Tinkerb and Stephen Caddick*a
Received 26th February 2010, Accepted 16th April 2010
First published as an Advance Article on the web 30th April 2010
DOI: 10.1039/c0cc00142b
A highly efficient, practical and flexible two-step asymmetric
synthesis of the b2-selective b-blocker ICI 118,551 is reported,
allowing an unambiguous determination of the dependency
of biological activity with optical activity, revealing the
S,S-enantiomer to be the most potent.
compound is described as the erythro isomer.8,11 This leads to
the assignment of the relative stereochemistry of (ꢀ)-ICI
118,551 as S*,S* (Fig. 1). It appears that this compound
was incorrectly drawn and assigned in chemical abstracts12
as the R*,S* diastereomer and this is where the confusion in
the literature originates. For example docking studies on
models of the b-adrenergic receptors were carried out using
the incorrect threo diastereomer R*,S*-ICI 118,551.13 It is
worth noting that the threo diastereomer was also found to be
an active b2-selective blocker,8 so in this case the work
remains valid.
The b-adrenergic receptors (bARs) are G-protein-coupled
receptors (GPRCs) that exist as three subtypes, b1, b2 and
b3. The recently reported crystal structures for the b1AR1 and
b2AR2–4 have led to an upsurge in structural and biophysical
studies on these receptors. bAR antagonists (b-blockers) are
important drugs for the treatment of a range of diseases
including heart failure,5 ischemic heart disease,6 and hypertension.7
Most clinically used b-blockers are either selective for the
b1AR subtype or nonselective for the b1AR and b2AR.
However, b2AR-selective antagonism is useful as a pharma-
cological tool to probe the receptor and could potentially
represent an important pharmacotherapy in its own right.
By far the most potent and selective b2AR antagonist cur-
rently known is the experimental compound ICI-118,551.8–10
ICI 118,551 has been reported to have 550 times higher affinity
for b2AR over b1AR.9 The structure of ICI 118,551 consists
of an indane core with a pendant propanolamine chain
incorporating an a-methyl substituent (Fig. 1).
In the course of this investigation it became clear that the
absolute configuration of the more active enantiomer of ICI
118,551 had never been reported conclusively. The chromato-
graphic resolution of ICI 118,551 has been reported by Quaglia
et al., who reported a difference in the activity of the enantio-
mers, but without determination of the absolute stereochemis-
try.14 The authors of this paper postulated that the most active
enantiomer should be the 2S configuration by analogy with
other aryloxypropanolamine b-blockers.15 Unfortunately the
authors then suggest that the active enantiomer to be 2S,3R
which as discussed above is the wrong relative stereochemistry.
ICI 118,551 remains a very important pharmacological tool
for studying b-receptor biochemistry and the purpose of this
paper is to present our results which (a) clarify the ambiguity
relating to the biological activity of the enantiomers of ICI
118,551; (b) provide a practical and flexible asymmetric syn-
thesis of ICI 118,551; and (c) provide an assessment of the
b1 : b2 receptor antagonism of each enantiomer of ICI
118,551 compared with the racemate. The results of this work,
we believe, will aid investigators using ICI 118,551 and the
simplicity of the synthetic route will offer opportunities for
generating a wide range of analogues for biological applica-
tions and the development of therapeutics.
We were interested in ICI 118,551 as a basic starting
point for a programme of molecular design to develop new
b2-selective antagonists. However we were surprised to find
that there was ambiguity in the literature reports describing
the stereochemistry of ICI 118,551. In the original patent
describing (ꢀ)-ICI 118,551, and related synthetic work, the
A concise asymmetric synthesis of ICI 118,551 was developed
(Scheme 1). Epoxide 1 was prepared via a known one-pot
Sharpless asymmetric epoxidation-in situ tosylation sequence
on trans crotyl alcohol.16 Displacement of the tosylate with the
commercially available indanol 2 using caesium carbonate as
the base led to epoxide 3 in high yield. The enantiomeric purity
was determined by chiral HPLC (>95% ee). Ring-opening of
the epoxide with isopropylamine gave (2S,3S)-ICI 118,551, for
which a crystal structure was obtained and is shown below.
The synthetic route is extraordinarily short from the commer-
cially available indanol 2 and offers flexibility, given the
commercial availability of amines.
Fig.
1
(ꢀ)-ICI 118,551 shown with the correct S*,S* relative
stereochemistry.
a Department of Chemistry, University College London,
20 Gordon St, London, UK. E-mail: j.r.baker@ucl.ac.uk;
Fax: +44 (0)2076797463; Tel: +44 (0)2076792653
b Department of Medicine, University College London, 5 University St,
London, UK
w We would like to dedicate this paper to the memory of Sir James
Black who instigated this work as part of a larger bAR study at UCL.
z Electronic supplementary information (ESI) available: Full experi-
mental details are provided. See DOI: 10.1039/c0cc00142b
ꢁc
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the two receptors. For example, the gain in affinity of
the (2S,3S) enantiomer was greater at b1AR than b2AR.
This unexpected observation may suggest a complementary
binding mode for the two enantiomers, and we are currently
investigating this possibility further.
In conclusion we have developed a highly efficient asymmetric
synthesis of ICI 118,551, and confirmed conclusively that the
(2S,3S) enantiomer is the most potent. While varying in
activities the 2S,3S and 2R,3R enantiomers are both selective
for the b2-adrenoceptor over the b1-adrenoceptor. We are
currently investigating the apparent drop in selectivity shown
by the individual enantiomers relative to the racemate.
We would like to thank RCUK and the Dorset Foundation
for funding, the EPSRC mass spectrometry service, and Prof.
Derek Tocher for obtaining the crystallography data.
Scheme 1 Asymmetric synthesis and crystal structure of (2S,3S)-ICI
Notes and references
118,551. Hydrogens shown on chiral centres for clarity.
1 T. Warne, M. J. Serrano-Vega, J. G. Baker, R. Moukhametzianov,
P. C. Edwards, R. Henderson, A. G. W. Leslie, C. G. Tate and
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Table 1 The binding affinities (pKi) of racemic and enantiopure
preparations of ICI-118,551 for b1AR and b2AR, and their b2AR/
b1AR-selectivity ratios, as determined by [3H]CGP-12177 competition
binding
pKi
b2AR-selectivity
ratio
b1AR
b2AR
Preparation
n
(ꢀ)-ICI-118,551
3
4
3
6.54 ꢀ 0.09 9.22 ꢀ 0.1 474
7.51 ꢀ 0.13 9.27 ꢀ 0.06 58
5.63 ꢀ 0.16 8.00 ꢀ 0.06 234
(2S,3S)-ICI-118,551
(2R,3R)-ICI-118,551
By simply changing the chiral ligand in the Sharpless
epoxidation to L-(+)-diisopropyltartrate we repeated this
synthesis to afford (2R,3R)-ICI 118,551. The two enantiomers
of ICI 118,551, in addition to the racemate,15 were then tested
for their activity and selectivity for the b1AR vs. b2AR. This
was carried out using a [3H]CGP-12177 competition assay on
HEK293 membranes expressing either b1AR or b2AR.
(ꢀ)-ICI-118,551 bound with high affinity to b2AR and
considerably lower affinity to b1AR, giving it a b2AR/b1AR
selectivity ratio of 474 (Table 1). These results are in good
agreement with those previously published.9,17 At both bARs
(2S,3S)-ICI-118,551 was found to bind with higher affinity,
and (2R,3R)-ICI-118,551 was found to bind with lower affinity,
than the racemate. The differences in pKi values between the
two enantiomers were highly statistically significant at both
the receptors. We can thus conclusively confirm that the
(2S,3S) enantiomer has the greatest bAR binding affinity.
Interestingly, for both enantiomers the b2AR-selectivity was
found to be lower compared to the racemate. This was due to
the relative changes in binding affinity being nonequivalent at
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12 CAS have confirmed this to be the case following communication
with the authors of this paper and have now moved the name ICI
118551 to a different record, RN 72795-26-7, which reflects the
correct S*,S* stereochemistry.
13 K. E. Furse and T. P. Lybrand, J. Med. Chem., 2003, 46,
4450–4462.
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L. A. Morrone, J. Chromatogr., A, 1994, 666, 289–293.
15 The racemate was accessed by making up a 1 : 1 mixture of the
two enantiomers.
16 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune
and K. B. Sharpless, J. Am. Chem. Soc., 1987, 109,
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This journal is The Royal Society of Chemistry 2010
3954 | Chem. Commun., 2010, 46, 3953–3954