Download MendeleyDiscovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.
Gandhi, V.B., Luo, Y., Liu, X., Shi, Y., Klinghofer, V., Johnson, E.F., Park, C., Giranda, V.L., Penning, T.D., Zhu, G.D.(2010) Bioorg Med Chem Lett 20: 1023-1026
- PubMed: 20045315
- DOI: https://doi.org/10.1016/j.bmcl.2009.12.042
- Primary Citation of Related Structures:
3L3L - PubMed Abstract:
Through conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, a series of PARP inhibitors was designed for appropriate orientation for binding to the PARP surface. This series of compounds with a 3-oxoisoindoline-4-carboxamide core structure, displayed modest to good activity against PARP-1 in both intrinsic and cellular assays. SAR studies at the lactam nitrogen of the pharmacophore have suggested that a secondary or tertiary amine is important for cellular potency. An X-ray structure of compound 1e bound to the protein confirmed the formation of a seven-membered intramolecular hydrogen bond. Though revealed previously in peptides, this type of seven-membered intramolecular hydrogen bond is rarely observed in small molecules. Largely due to the formation of the intramolecular hydrogen bond, the 3-oxoisoindoline-4-carboxamide core structure appears to be planar in the X-ray structure. An additional hydrogen bond interaction of the piperidine nitrogen to Gly-888 also contributes to the binding affinity of 1e to PARP-1.
Organizational Affiliation:
Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. viraj.b.gandhi@abbott.com
