5608
J. Blagg et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5605–5608
Table 3
Activity and lipophilicity data for heterocyclic templates
X
N
R
Y
N
O
O
125I binding affinity IC50 (nM)
Functional activity IC50 (nM)
LogDb
a
a
Compound
R
X
Y
15
16
17
18
19
20
21
1-Naphthyl
H
H
H
H
CH2(p-Cl-phenyl)
CH2(p-Cl-phenyl)
CH2-cyclo-hexyl
CH2(p-Cl-phenyl)
790
90
500
47
>1000
nd
nd
877
nd
850
nd
>5
nd
4.1c
>4
3-Benzo-thiophene
3-Benzo-thiophene
3-Methoxy-phenyl
3-Benzo-thiophene
3-Benzo-thiophene
3-Benzo-thiophene
3.8d
4.0
3,4-diCl-phenyl
3-Cl-phenyl
Me
325
CH2(p-Cl-phenyl)
90
nd
4.6
a
Values are means of at least two experiments.
LogD measured at pH 7.4 in octanol/neutral buffer.
pKa estimated as 6.9 using the ACD Labs prediction software.
b
c
d
pKa estimated as 7.3 using the ACD Labs prediction software. nd, not determined.
Christopher Luckhurst, Paul Glossop, Lindsey Sprigens, David Beal,
Marie-Blanche Harnois and Alison Harper.
Both the triazole 22 and the much more basic imidazoline 23 were
inactive. The heterocyclic core compounds were not as potent as
hoped for, and the only way to install higher potency into them
would be to increase their size and lipophilicity. We had obtained
no encouragement that a basic centre could rescue the physical
properties of the compounds and achieve our target goal of LogD
<4. The compounds which came closest to meeting these criteria
were 13 and 15. The payoff in installing polarity into these struc-
tures was only modest potency. Sub-10 nM potency was only
achieved in compounds which had a LogD >4. Our conclusions from
this piece of work were similar to those after the initial investiga-
tions described in the previous paper, that the C5a receptor did
not tolerate strong polarity or basicity in the transmembrane region
where we assumed our molecules were binding. As such, it would
be difficult to achieve an appropriate balance of potent C5a receptor
binding potency and physical properties commensurate with oral
dosing in this series.
References and notes
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Our studies and conclusion on this series of C5a receptor antag-
onists provides another case to support the increasingly popular
view11 that development candidates and drugs often closely
resemble the starting point for the programme and the counter-
point that it is very difficult to turn a fundamentally flawed lead
into a quality development candidate.
5. See previous letter in this issue.
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10. CD11b upregulation was measured in heparinised human blood by flow
cytometry following C5a stimulation for 5 min at 37 °C. C5aR antagonists were
pre-incubated with blood for 1 min at 37 °C prior to C5a stimulation.
11. Proudfoot, J. R. Bioorg. Med. Chem. Lett. 2002, 12, 1647.
Acknowledgments
The authors gratefully acknowledge the technical support of
Chris Carr, Kevin Coote, Katherine Grant, Vicky Stubbs, Tony Chuck,