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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 3; pp. 1023 - 1026
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-02-2010; Elsevier
• Subjects: 3-Oxoisoindoline-4-carboxamide; Amides - chemistry; Amides - metabolism; Amides - therapeutic use; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Crystallography, X-Ray; Drug Discovery - methods; General aspects; Inhibitor of poly(ADP-ribose) polymerase; Isoindoles - chemistry; Isoindoles - metabolism; Isoindoles - therapeutic use; Medical sciences; Neoplasms - drug therapy; Neoplasms - enzymology; PARP inhibitor; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - metabolism; Structure-Activity Relationship; 3-Oxoisoindoline-4-carboxamide; PARP inhibitor; Inhibitor of poly(ADP-ribose) polymerase; Antineoplastic agent; Molecular structure; Enzyme; Transferases; Glycosyltransferases; Lactam; Enzyme inhibitor; Molecular interaction; X ray diffraction; Isoindole derivatives; NAD; Structure activity relation; Piperidine derivatives; ADP-ribosyltransferase; Carboxamide; Pentosyltransferases; Hydrogen bond; Crystalline structure
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.12.042

We have discovered a series of compounds with a 3-oxoisoindoline-4-carboxamide core structure as potent PARP inhibitors. The highlight of the core is a conformational restriction of a benzamide by formation of a seven-membered hydrogen-bond with an oxindole carbonyl group, with compound
1e identified as the most potent in vitro PARP-1 inhibitor.
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.