Synthesis and Structure—Activity Relationships of Novel Poly(ADP‐Ribose) Polymerase‐1 Inhibitors.

Abstract

Polymerase-1 Inhibitors. -High throughput screening of an internal library identifies pyrrolocarbazole (VIIa) as a potent PARP-1 inhibitor. Structural modifications around this novel PARP-1 template identifies the key pharmacophore elements necessary for PARP-1 inhibition. The cyclopentyl ring fits into a steric pocket with the enzyme and is required for potency. The indole NH-group forms a significant H-bond with PARP-1. The truncated pyrrole imide (XIb) is equipotent to (VIIa), indicating that the B-ring is not required, and represents a novel small molecule PARP-1 scaffold. -(TAO*, M.; PARK, C. H.; BIHOVSKY, R.; WELLS, G. J.; HUSTEN, J.; ATOR, M. A.; HUDKINS, R. L.; Bioorg. Med. Chem. Lett. 16 (2006) 4, 938-942; Cephalon Inc., West Chester, PA 19380, USA; Eng.) -H. Hoennerscheid

PARP inhibitors: polypharmacology versus selective inhibition

“…At the start of 2001, Cephalon filed patent applications describing a series of pyrrolo carbazole lactams as potent PARP inhibitors on the basis of highthroughput screening [43]. Lead-optimization combined with determination of structure-activity relationships allowed researchers at Cephalon to improve the potency and solubility of the core structure of this series of compounds, leading to CEP-8983 (4), a high potency and moderately soluble PARP inhibitor (K i = 20 nM) [44]. The issue of solubility was next solved by designing a soluble pro-drug of the inhibitor (CEP-9722) (5).…”

Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology

“…The relatively low potency of these agents has led to development of more potent and specific proprietary PARP inhibitors. The optimization of PARP inhibitor structures to increase potency and specificity, such as benzimidazoles and dihydroisoquinolinones (39), pyrrolocarbazoles (40), and phthalazinones (41,42), have been published by some of the leading industry groups. An excellent review of different chemical classes of PARP inhibitors has been written by Southan and Szabo (43).…”

Serendipitous Discovery of a Prodrug of a PARP‐1 Inhibitor

“…Compounds 14 and 1 were also tested in a cell-based assay that measured their ability to attenuate the depletion of NAD + levels in PC12 cells following activation of PARP by DNA damage with hydrogen peroxide (9,10). In this assay, the superior activity of compound 14 in comparison with compound 1 was apparent (Figure 2).…”

“…Previously, our laboratories reported the identification of a novel pyrrolocarbazole compound 1, as a potent PARP-1 inhibitor (Figure 1, IC 50 36 nM) from screening of our corporate chemical library (9,10). Although compound 1 displayed potency, its poor drug-like characteristics, especially its extremely low solubility in various acceptable vehicles, made it difficult to perform in vivo experiments.…”

“…Target compounds were evaluated against recombinant human poly (ADP-ribose) polymerase-1 in an in vitro enzyme assay (carried out in triplicate) as described previously (9,10). Table 1 describes the biologic activities of compounds 3-15 as well as the parent compound 1.…”