J. Ishida et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4221–4225
Table 3. PARP-1 inhibition of phenanthridin-6(5H)-one derivatives
4225
O
NH
R1
R2
Compound
IC50 (nM)
21a
R1 =
R2 = H
46
N
21b
24a
R1 =
R2 = H
R2 =
119
16
N
R1 = H
N
N
O
24b
5
R1 = H
R2 =
23
110
3. (a) Laplaca, M. C.; Zhang, J.; Raghupathi, R.; Li, J. H.;
Smith, F.; Bareyre, F. M.; Snyder, S. H.; Graham, D. I.;
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Adbelkarim, G. E.; Harms, C.; Katchanov, J.; Dirnagl,
midinone and phthalazin-1(2H)-one derivatives, the
phenyl ring of the 4-phenyl-1,2,3,6-tetrahydropyridine
moiety may permit this vital fixation of the nitrogen
atom by efficiently binding the AD site.
´
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In conclusion, we have demonstrated that 4-phenyl-
1,2,3,6-tetrahydropyridine is an excellent fragment to im-
prove PARP-1 inhibitory potency by connecting it via
alkyl spacers to published scaffolds, such as pyrimidine-
4-one, phenanthridin-6(5H)-one, and phthalazin-1(2H)-
one. We have obtained highly potent PARP-1 inhibitors
10b, 10d, 15a, 21a, and 24a. This utilization of 4-phenyl-
tetrahydropyridine could be extended to other published
PARP-1 inhibitors containing scaffolds that mimic benz-
amide. Detailed SAR, pharmacokinetic, and in vivo data
for these derivatives will be reported in due course.
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Acknowledgment
We thank Dr. David Barrett for his critical reading of
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