22775-37-7Relevant articles and documents
Discovery and structure-activity relationships of modified salicylanilides as cell permeable inhibitors of poly(ADP-ribose) glycohydrolase (PARG)
Steffen, Jamin D.,Coyle, Donna L.,Damodaran, Komath,Beroza, Paul,Jacobson, Myron K.
experimental part, p. 5403 - 5413 (2011/10/02)
The metabolism of poly(ADP-ribose) (PAR) in response to DNA strand breaks, which involves the concerted activities of poly(ADP-ribose) polymerases (PARPs) and poly(ADP-ribose) glycohydrolase (PARG), modulates cell recovery or cell death depending upon the level of DNA damage. While PARP inhibitors show high promise in clinical trials because of their low toxicity and selectivity for BRCA related cancers, evaluation of the therapeutic potential of PARG is limited by the lack of well-validated cell permeable inhibitors. In this study, target-related affinity profiling (TRAP), an alternative to high-throughput screening, was used to identify a number of druglike compounds from several chemical classes that demonstrated PARG inhibition in the low-micromolar range. A number of analogues of one of the most active chemotypes were synthesized to explore the structure-activity relationship (SAR) for that series. This led to the discovery of a putative pharmacophore for PARG inhibition that contains a modified salicylanilide structure. Interestingly, these compounds also inhibit PARP-1, indicating strong homology in the active sites of PARG and PARP-1 and raising a new challenge for development of PARG specific inhibitors. The cellular activity of a lead inhibitor was demonstrated by the inhibition of both PARP and PARG activity in squamous cell carcinoma cells, although preferential inhibition of PARG relative to PARP was observed. The ability of inhibitors to modulate PAR metabolism via simultaneous effects on PARPs and PARG may represent a new approach for therapeutic development.
Synthesis of ω-Fluoroalkoxy and Alkoxy Derivatives of Raclopride: Evaluation as Radioligands for PET study of Cerebral Dopamine D2 Receptors
Banks, William R.,Moerlein, Stephen M.,Parkinson, David,Welch, Michael J.
, p. 150 - 173 (2007/10/03)
A series of analogues of the dopamine D2 receptor antagonist raclopride were evaluated as radiopharmaceuticals for positron emission tomography (PET). In vitro assays indicate that the D2 affinity of the ligands are descreased by replacement of the 2-methoxy group of raclopride with ω-fluoroalkoxy substituents, and increased by removal of the 6-hydroxy substituent. The 2-fluoroethoxy derivative of deshydroxy raclopride, [(S)-2-[(3,5)-dichloro-2-(2'-fluoroethoxy)benzamido)-methyl]-1-ethylpyrrolidine], exhibited a D2 affinity (Ki = 12nM) close to that of raclopride itself (Ki = 9.5 nM). A one-step radiosynthesis of the fluorine-18 labeled analogue of this ligand with specific radioactivity > 2 Ci/μmol and 35 percent radiochemical yield (decay-corrected) was developed; there was poor receptor-specific localization of this radioligand in vivo in rats, however. These results underscore the inadequacy of in vitro receptor assays as the sole screening test for PET radiopharmaceuticals. Future development of this series of ligands should emphasize placement of the fluorine-18 label at an aromatic site remote from the intramolecular hydrogen-bonding sites necessary for receptor-active conformations
