Abstract
The synthesis, activity and physical properties of two series of novel potent tetrahydro-1(2H )-isoquinolinone based PARP-1 inhibitors are described. The new structural classes with a non-planar ring system interact specifically with the PARP-1 protein at the nicotinamide-binding site.
Key words
medicinal chemistry - PARP inhibitors - structure-activity relationship - isoquinolinones - crystal structure
References 1 New address: S. Peukert, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA; E-Mail: stefan.peukert@novartis.com.
2 Smith S.
Trends Biochem. Sci.
2001,
26:
174
3 Virag L.
Szabo C.
Pharmacol. Rev.
2002,
45:
73
4 Eliasson MJL.
Sampei K.
Mandir AS.
Hurn PD.
Traystman RJ.
Bao J.
Pieper A.
Wang Z.-Q.
Dawson TM.
Snyder SH.
Dawson VL.
Nat. Med.
1997,
3:
1089
5a Komjati K.
Mabley JG.
Virag L.
Southan GJ.
Salzman AL.
Szabo C.
Int. J. Mol. Med.
2004,
273:
373
5b Ferraris D.
Ko YS.
Pahutski T.
J. Med. Chem.
2003,
46:
3138
5c Calabrese CR.
Almassy R.
Barton S.
Batey MA.
Calvert AH.
Canan-Koch S.
Durkacz BM.
Hostomsky Z.
Kumpf RA.
Kyle S.
Li J.
Maegley K.
Newell DR.
Notarianni E.
Stratford IJ.
Skalitzky D.
Thomas HD.
Wang L.-Z.
Webber SE.
Williams KJ.
Curtin NJ.
J. Natl. Cancer Inst.
2004,
96:
56
6 Ruf A.
De Murcia G.
Schulz GE.
Biochemistry
1998,
37:
3893
7 Banasik M.
Komura H.
Shimoyama M.
Ueda K.
J. Biol. Chem.
1992,
267:
1569
8 Li J.-H, Tays KL, and Zhang L. inventors; Guildford Pharmaceuticals WO 9911624.
; Chem. Abstr. 1999 , 130 , 218328
9 Peukert S.
Schwahn U.
Exp. Opin. Ther. Pat.
2004,
14:
1531
10 Falk H.
Suste A.
Monatsh. Chem.
1994,
125:
325
11 Netherton MR.
Fu GC.
Org. Lett.
2001,
3:
4295
12 Meudt A. inventors; Clariant GmbH, WO 03033503.
; Chem. Abstr. 2003 , 138 , 321392
13 i -PrOH as precipitant, following the protocol of Jung et al.: Jung S.
Miranda EA.
De Murcia JM.
Niedergang C.
Delarue M.
Schulz GE.
DeMurcia GM.
J. Mol. Biol.
1994,
244:
114 . Inhibitor complexes were obtained by soaking native crystals with the appropriate inhibitors. The space group and cell dimensions of the crystals obtained were the same as in the published crystal structures. We obtained well diffracting crystals, diffracting to 2.2 and 2.1 Å resolutions, respectively. We did not observe any major differences between our PARP structures and the PARP structures present in the PDB
14 Ruf A.
De Murcia JM.
De Murcia GM.
Schulz GE.
Proc. Natl. Acad. Sci. U.S.A.
1996,
93:
7481
