Quinazolinone PARP inhibitors

PARP inhibitors have been synthesized (11) and are shown in Figs. 11.4 and 11.5. Some of them have been tested in stroke models with good results in terms of preventing infarction (12-18). Most of the inhibitors are based on the structure of nicotinamide and therefore bind to the nicotinamide site of PARP. Several inhibitors are well known, such as nicotinamide, benzamide, and 3-aminobenzamide (19,20). However, new quinazolinone, phen-anthradinone, and other inhibitors are being investigated. Nicotinamide has a of about 5 xM for PARP (19). Activity is decreased in 6-aminonicotinamide, isonicotinamide, 1-methylnicotinamide, 5-methylnicotinamide, 8-methylnicotinamide, and thionicotinamide (Table 11.1 >... 

The amide ring-closure method has also been used in a solid-phase combinatorial synthesis of inhibitors of poly(ADP-ribose)polymerase (PARP-1). The penultimate intermediates 770 were cleaved from the resin with trifluoroacetic acid, and this was followed by ring closure with sodium hydroxide, at room temperature, to give the quinazolinone products 771 <2004JME4151>. 

Griffin RJ, et al. Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA 156. repair enzyme poly(ADP-ribose) polymerase (PARP). J. Med. 

A series of quinazolinone inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) was prepared. It was shown that, in general, compounds linked with the cyclopentene 43 were more metabolically stable and had lower clearance rates than the corresponding compounds linked with linear alkyl linkers, as is 42. Being able to block the primary site of metabolism also translated into having more efficacious compounds in vivo with superior B/P ratios. Compound 42 had a B/P ratio of 0.4 after oral administration, while cyclopentene 43 had a B/P ratio of 4.1. 

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