Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H )-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells
IRBM, Merck Research Laboratories Rome, Pomezia 00040, Rome, Italy.Bioorganic & medicinal chemistry letters (Impact Factor: 2.42). 11/2009; 20(3):1100-5. DOI: 10.1016/j.bmcl.2009.11.087
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
- Annual reports in medicinal chemistry 01/2010; 45:229-243. DOI:10.1016/S0065-7743(10)45014-9 · 1.36 Impact Factor
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ABSTRACT: The present work reports an energetic and structural study of 2-fluoro-, 3-fluoro-, and 4-fluorobenzonitrile. The standard molar enthalpies of formation, in the condensed phase, of the three isomers were derived from the standard molar energies of combustion, in oxygen, at T = 298.15 K. The standard molar enthalpies of vaporization or sublimation (for 4-fluorobenzonitrile), at T = 298.15 K, were measured using high-temperature Calvet microcalorimetry. The combination of these two parameters yields the standard molar enthalpies of formation in the gaseous phase. The vapor-pressure study of the referred compounds was performed by a static method, and the enthalpies of phase transition derived from the application of the Clarke and Glew equation. Theoretically estimated gas-phase enthalpies of formation, basicities, proton and electron affinities, and adiabatic ionization enthalpies were calculated from the G3MP2B3 level of theory. In order to evaluate the electronic properties, the geometries were reoptimized at MP2/cc-pVTZ level, and the QTAIM and NICS were computed. On the basis of the donor-acceptor system, another approach for evaluating the electronic effect for these compounds, using the NBO is suggested. The UV-vis spectroscopy study for the three isomers was performed. The intensities and the band positions were correlated with the thermodynamic properties calculated computationally.The Journal of Organic Chemistry 03/2012; 77(9):4312-22. DOI:10.1021/jo3002968 · 4.72 Impact Factor
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ABSTRACT: A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41 showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that our PARP1 inhibitors significantly inhibited H2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of temozolomide was also observed for 41. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.Journal of Medicinal Chemistry 03/2013; 56(7). DOI:10.1021/jm301825t · 5.45 Impact Factor
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