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S. Peukert et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2823–2827
Table 3. Inhibitory activity of anthranilic amides against the Kv1.5 channel
Compound
R1
Z
pKa
IC50 [lM]
3x
3y
OMe
H
Me
Me
H
7.5
7.2
6.9
6.5
6.2
––
0.5
0.7
1.3
3.8
4.0
3.8
3z
H
3aa
3ab
3ac
F
Cl
H
Acetyl
CF3
Me
3ad
Me
––
46%@10lMa
3ae
Me
––
41%@10lMa
3af
Me
––
15%@10lMa
a Percent inhibition at 10 lM concentration.
3. Tomaselli, G. Heart Drug 2001, 1, 183.
an intramolecular hydrogen bond with the carbonyl
oxygen, which stabilizes a favorable active conformation.
4. Bril, A. Curr. Opin. Pharmacol. 2002, 2, 154.
5. Nishida, A.; Uemura, H.; Ogura, T.; Furusawa,
H.; Yabana, H.; Nakaya, H. Jpn. J. Pharmacol. 2000,
82, 1.
6. (a) Li, G. R.; Feng, J.; Yue, L.; Carrier, M.; Nattel, S.
Circ. Res. 1996, 78, 689; (b) Feng, J.; Wible, B.; Wang, Z.;
Nattel, S. Circ. Res. 1997, 80, 572; (c) Amos, G. J.;
Wettwer, E.; Metzger, F.; Li, Q.; Himmel, H. M.; Ravens,
U. J. Physiol. (Lond.) 1996, 491, 31.
To be considered as safe antiarrhythmics selectivity
toward the HERG channel is mandatory. As could be
shown with lead 3a and compounds 3i, 3n, 3q, and 3v,
there was no significant effect on the IKr current: 6%,
11%, 14%, 2%, and 1% inhibition at 10 lM concentra-
tion, respectively. Finally, for compound 3i oral bio-
availability in rats of 43% was found.
7. (a) Brendel, J.; Peukert, S. Expert. Opin. Ther. Patents
2002, 12, 1589; (b) Brendel, J.; Peukert, S. Curr. Med.
Chem.––CV & H Agents 2003, 1, 273.
In conclusion, we have discovered and optimized a new
class of potent Kv1.5 blockers based on a simple
anthranilic acid scaffold. The compounds show no sig-
nificant effect on the IKr current and are orally bio-
available, and are therefore promising drug substances
for a new and safe treatment of atrial fibrillation.
€
8. (a) Peukert, S.; Brendel, J.; Pirard, B.; Bruggemann, A.;
Below, P.; Kleemann, H.-W.; Hemmerle, H.; Schmidt, W.
J. Med. Chem. 2003, 46, 486; (b) Aventis Pharma
Deutschland GmbH, WO 0100573, 2001.
9. The conformational space of the seven Kv1.5 blockers
selected as training set for pharmacophore elucidation was
explored, using
a Monte Carlo Multiple Minimum
(MCMM) search protocol. This search protocol involved
the generation of maximum 5000 conformers by random
modifications of minimum 2 and maximum 7 torsion
angles at a time. Each generated conformer was sub-
mitted to 250 steps of conjugate gradient minimization.
Then, we discarded strained (more than 50 kJ molÀ1 above
the minimum) as well as duplicate conformations (distance
Acknowledgements
We wish to thank H. Plankenhorn, M. Schnierer, G.
Erhard, T. Spors, S. Peukert, and R. Weck for their
technical assistance in the synthesis of the compounds
€
and also A. Hertler and S. Muller for their assistance in
the pharmacological experiments.
ꢀ
cut off of 0.25 A between equivalent heavy atoms).
Conformers passing these filters were minimized until
convergence (convergence criterion 0.05 kJ AÀ1 molÀ1).
ꢀ
The energy was evaluated using the MacroModel 6.5
All–Atom force field. All the calculations were carried
out in water, as modeled by the generalized Born/solvent
accessible surface solvation model. The next step was to
select representative sets of conformers, using hierarchical
clustering on distances between all the potential pharma-
cophoric centers. Within each cluster, we chose the
minimum energy conformation as input for the automated
References and notes
1. Pratt, C. M.; Moye, L. A. Am. J. Cardiol. 1990, 65, 20B.
2. Waldo, A. L.; Camm, A. J.; Deruyther, H. Lancet 1996,
348, 7.