D. S. Gardner et al. / Bioorg. Med. Chem. Lett. 18 (2008) 586–595
595
Welch, P.; Covington, M.; Stowell, N.; Wadman, E.;
Davies, P.; Solomon, K.; Newton, R. C.; Trainor, G. L.;
Decicco, C. P.; Wacker, D. Bioorg. Med. Chem. Lett.
2004, 14, 1645; (b) Ab initio calculations were performed
as disclosed in the previous letter in this series (Ref. 1, and
then see Ref. 6 therein).
our two exercises in conformational analysis will inspire
medicinal chemists to design conformationally stable
acyclic alternatives to their heterocyclic and carbocyclic
drug targets.16
8. Tsai, H.; Roberts, J. D. Magn. Reson. Chem. 1992, 30,
828.
Supplementary data
9. It was at this point when the CCR3 discovery research
program was concluded. Thus there are no chemotaxis
inhibition data.
Supplementary data associated with this article can be
10. An interpretable 1H NMR spectrum of the TFA salt of
31Et could only be obtained in CD3OD. Other NMR
solvents yielded spectra with broadened peaks. It can be
envisaged, that H-bonding by CD3OD could prevent the
optimal conformer (Fig. 9a) from occurring. Surprisingly,
the pseudoephedrine portion of 31Et yielded coupling
constants that matched those that were calculated from
the conformation shown in Figure 9a (see Table below).
However, observed coupling constants for He–Hf differed
from those calculated. 1H NMR spectra and selective
1H–1H decoupled NMR spectra were obtained at both 500
References and notes
1. Santella, J. B., III; Gardner, D. S.; Yao, W.; Shi, C.;
Reddy, P.; Tebben, A. J.; Delucca, G. V.; Wacker, D. S.;
Watson, P. S.; Welch, P. K.; Wadman, E. S.; Davies, P.;
Solomon, K. A.; Graden, D. M.; Yeleswaram, S.; Man-
dlekar, S.; Kariv, I.; Decicco, C. P.; Ko, S. S.; Carter, P.
H.; Duncia, J. V. Bioorg. Med. Chem. Lett. 2008, 18, 576,
Available online 22 November, 2007.
2. For an abridged etiology of asthma and its eosinophil-
contributing component, see Supplement in Ref. 1.
3. The binding assay was carried out using 125I-labeled
eotaxin and CHO cells stably transfected with a gene
encoding human CCR3 as described in Ref. 4.
4. De Lucca, G. V.; Kim, U.-T.; Vargo, B. J.; Duncia, J. V.;
Santella, J. B., III; Gardner, D. S.; Zheng, C.; Liauw, A.;
Wang, Z.; Emmett, G.; Wacker, D. A.; Welch, P. K.;
Covington, M.; Stowell, N. C.; Wadman, E. A.; Das, A.
M.; Davies, P.; Yeleswaram, S.; Graden, D. M.; Solomon,
K. A.; Newton, R. C.; Trainor, G. L.; Decicco, C. P.; Ko,
S. S. J. Med. Chem. 2005, 48, 2194.
1
1
and 700 MHz. In addition, H–1H and H–13C 2D NMR
spectra were obtained at 500 MHz.
He
Hd
H
Ha
OH
OH
N
N
H
N
H
N
N
N +
N
-
CF3CO2
CH3
O
Hb
Hc
Hf
Hx-Hy Calculated Jx-y
,
Measured Jx-y
,
(Hz)
(Hz)
5. The binding assay was carried out using 125I-labeled
eotaxin and CHO cells stably transfected with a gene
encoding a chimeric receptor, consisting of the intracellu-
lar domain of human CCR2 with the extracellular and
transmembrane domains of human CCR3. This variation
was found to give results nearly identical to those obtained
using the native CCR3 receptor as shown below:
Ha-Hb
Hc-He
Hd-He
He-Hf
9.6
10
2.5
10
5
3.2
11.0
10.7
11. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635.
12. Miyazaki, T.; Han-ya, Y.; Tokuyama, H.; Fukuyama, T.
Synlett 2004, 477.
13. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morik-
awa, K.; Wang, Z.-M.; Xu, D.; Zhang, X.-L. J. Org.
Chem. 1992, 57, 2768.
14. Imashiro, T. R.; Sakurai, O.; Yamashita, T.; Horikawa,
H. Tetrahedron 1998, 54, 10657.
15. Prepared by a slight modification of the procedure found
in Chen, P.; Cheng, P. T. W.; Spergel, S. H.; Zahler, R.;
Wang, X.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P.
Tetrahedron Lett. 1997, 38, 3175.
Inhibitory effects
of 1 on 125I-labelled
100
eotaxin on
hCCR3/CCR2
50
chimera transfected
CHO cells. IC50
=
0
0.4 nM, n=8 Each
point represents
mean SEM.
-7 -6 -5 -4 -3 -2 -1
Log cin,uM
0
Taken from U.S. 2005/0123972, published June 9, 2005.
6. Ko, S. S.; Wang, J.; Clark, C. M.; Srivastava, A. S.;
Chaudhari, A.; Batt, D. G.; Houghton, G.; DeLucca, G.;
Duncia, J. V.; Welch, P. K.; Wadman, E. A.; Davies, P.;
Solomon, K. A.; Graden, D. M.; Yeleswaram, S.; Decicco,
C. P.; Carter, P. H., manuscript in preparation.
16. For approaches to designing conformationally rigid
acyclic scaffolds which mimic conformationally preorga-
nized acyclic natural products, see (a) Hoffmann, R. W.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1124; (b)
Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 2000,
39, 2054; (c) Schopfer, U.; Stahl, M.; Brandl, T.;
Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1997,
36, 1745.
7. (a) Varnes, J. G.; Gardner, D. S.; Santella, J. B.; Duncia,
J. V.; Estrella, M.; Watson, P. S.; Clark, C. M.; Ko, S. S.;