Poly polymerase-1 PARP inhibitors

Currently flow-cytometric methods are also under development to examine effects of various inhibitors of PARP (poly(ADP-ribose)polymerase) that are in preclinical development or clinical trials and use native or stimulated PARP activity in peripheral blood mononuclear cells. 

Chatterjee PK, Thiemermann C. Poly(ADP-ribose) polymerase inhibitors and acute renal failure. In Zhang J, ed. Therapeutic Utilities of PARP Inhibitors. Boca Raton CRC Press, 2002 149-168. 

Ataxia telangiectasia mutated (ATM), poly(ADP ribose) polymerase (PARP), DNA-dependent protein kinase, DNA replication factor C, DNA topoisomerase I, DNA fragmentation factor (DFF)45, inhibitor of caspase-activated DNAse (ICAD), lamins A, Bl, and C TRAF-1, Rafl, Ras, GAP, GDP dissociation inhibitor of Rho family GTPases, phospholipase A2, Statl... 

Schelman WR, Sandhu SK, Moreno GV et al (2011) First-in-human trial of a poly(ADP)-ribose polymerase (PARP) inhibitor MK-4827 in advanced cancer patients with antitumor activity in BRCA-deficient tumors and sporadic ovarian cancers (soc). J Clin Oncol 29 abstr 3102... 

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>. 

Since isoquinolinones are known to be very potent inhibitors of poly(ADP-ribose)polymerase (PARP), thieno[3,4-( ]pyridin-4-ones have been studied for their potential as PARP inhibitors <1999BMC297>. Early studies indicate that the sulfur analogues also act as potent PARP inhibitors. Thienopyridine diazonium salts can be converted into heterocyclic dyes that are useful as disperse dyes for polyester fabrics <2005DP(64)223, 2006DP(70)60>. 

Costantino, G., Macchiarulo, A., Camaio-ni, E., Pellicciari, R. Modeling of Poly(-ADP-ribose)polymerase (PARP) Inhibitors. Docking of Ligands and Quantitative Structure-Activity Relationship Analysis. J. Med. Chem. 2001, 44, 3786-3794. 

Poly (ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks (Calabrese et al, 2004). Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. But classical PARP-1 inhibitors have limited clinical utility. AG14361 is, to our knowledge, the first high-potency... 

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. 

Poly(ADP-ribose) polymerase (PARP) plays an important role in a number of cellular processes, including DNA repair. Elevated PARP has been observed in some cancer patients, and combination of PARP inhibitors with cytotoxic agents has demonstrated S3mergistic effects in preclinical models. Thus, PARP inhibitors in combination with conventional DNA-damaging cancer treatments may offer a new approach to various cancers. AG-14699 [26] is the lead in a series of inhibitors of PARP and is being evaluated in phase II studies for the potential treatment of cancer including melanoma, breast cancer, and ovarian cancer. 

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