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02 May 2003

5-Aminoisoquinolin-1-one and other water-soluble PARP inhibitors

M. Threadgill, J. Berry, S. Ferrer, I. Parveen, A. Shinkwin, E. Woon

Med Sci Monit 2003; 9(1): 71- :: ID: 15214

Abstract

Inhibitors of the activity of PARP have applications in the treatment of many disease states. Most of the known inhibitors of PARP mimic the nicotinamide of the substrate NAD+. The consensus pharmacophore for PARP inhibitors is a primary or secondary benzamide with N–H conformationally constrained anti to the carbonyl-arene bond. However, this can also be considered as a ‘pharmacophore’ for insolubility in water. In this presentation, the results of our work on extending this pharmacophore into heterocyclyl carboxamides, into more water-soluble inhibitors and into potential prodrugs will be outlined. For example, 5-substituted isoquinolin-1-ones and 2, 8-substituted quinazolin-4-ones are known [1,2] to be potent inhibitors of PARP; we have shown [3] that the analogous thieno [3,4-c]pyridin-4(5H)-ones and thieno [3,4-d]pyrimidin-4(3H)-ones are also strongly active. New synthetic routes to 5-aminoisoquinolin-1-one (5-AIQ) have been developed [4], making this inhibitor more readily available. 5-AIQ shows IC50 = 250 nM against PARP activity in a broken nuclear preparation; its corresponding IC50 against a mono-ADP-ribosyl transferase (diphtheria toxin) is 80 KM, making 5-AIQ highly selective for PARP. This compound is highly water-soluble as its hydrochloride, making it suitable for rapid i.v. administration. 5-AIQ protects against organ damage in a rat model of haemorrhagic shock at the remarkably low dose of 30 KgŠKg–1. It is similarly active in vivo in models of myocardial infarction and acute lung inflammation. Potential bioreductively activated prodrugs of this and other isoquinolin-1-ones have been synthesised [5,6] and are shown to release drug rapidly in experimental systems; these include 2-(2-nitroimidazol-5-ylmethyl)isoquinolin-1-ones and 1, 2-dimethyl-3-(isoquinolin-1-yloxymethyl)-5-methoxyindole-4, 7-diones. Further developments from these leads are under active research. References: 1.Suto MJ, Turner WR et al: Anti-Cancer Drug Design, 1991; 7: 107 2.Griffin RJ, Pemberton LC et al: Anti-Cancer Drug Design, 1995; 10: 507 3.Shinkwin AE, Whish WJD, Threadgill MD: Bioorg Med Chem, 1999; 7: 297 4.McDonald MC, Mota-Filipe H, Wright JA et al: Br J Pharmacol, 2000; 130: 843 5.Parveen I, Naughton DP et al: Bioorg Med Chem Lett, 1999; 9: 2031 6.Ferrer S, Naughton DP, Parveen I et al: J Chem Soc Perkin Trans, 2002; 1: 335

Keywords: 5-Aminoisoquinolin-1-one, thieno [3,4-c]pyridin-4(5H)-one, prodrug, Solubility, Reperfusion

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750