Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer

作者：Gandhi Viraj B^*; Luo Yan; Liu Xuesong; Shi Yan; Klinghofer Vered; Johnson Eric F; Park Chang; Giranda Vincent L; Penning Thomas D; Zhu Gui Dong

来源：Bioorganic & Medicinal Chemistry Letters, 2010, 20(3): 1023-1026.

DOI：10.1016/j.bmcl.2009.12.042

• PARP inhibitor
• Inhibitor of poly(ADP-ribose) polymerase
• 3-Oxoisoindoline-4-carboxamide

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.

• 出版日期2010-2-1