Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer.
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.
Gandhi
Viraj B
VB
Cancer Research, GPRD, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. viraj.b.gandhi@abbott.com
Luo
Yan
Y
Liu
Xuesong
X
Shi
Yan
Y
Klinghofer
Vered
V
Johnson
Eric F
EF
Park
Chang
C
Giranda
Vincent L
VL
Penning
Thomas D
TD
Zhu
Gui-Dong
GD
D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D054833:Isoindoles / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D054833:Isoindoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases