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  3. The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

The discovery and synthesis of novel adenosine substituted 2,3-dihydro-1H-isoindol-1-ones: potent inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1)

  • Bioorg Med Chem Lett. 2004 Jan 5;14(1):81-5. doi: 10.1016/j.bmcl.2003.10.007.
Prakash G Jagtap 1,  Garry J Southan,  Erkan Baloglu,  Siya Ram,  Jon G Mabley,  Anita Marton,  Andrew Salzman,  Csaba Szabó
Affiliations

Affiliation

  • 1 Inotek Pharmaceuticals Corporation, 100 Cummings Center, Suite 419E, Beverly, MA 01915, USA. [email protected]
PMID: 14684303 DOI: 10.1016/j.bmcl.2003.10.007
Abstract

A series of novel 4-(N-acyl)-2,3-dihydro-1H-isoindol-1-ones have been prepared from methyl-3-nitro-2-methylbenzoate and linked through various spacers to the adenosine derivatives 11 and 12. We found that potent inhibition of poly(ADP-ribose)polymerase-1 (PARP-1) was achieved when isoindolinone was linked to adenosine by a spacer group of a specific length. Introduction of piperazine and succinyl linkers between the isoindolinone and adenosine core structures resulted in highly potent compounds 8a and 10b, which showed IC(50) values of 45 and 100 nM, respectively.

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