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Discovery of 2-{4-[(3 S)-Piperidin-3-yl]phenyl}-2 H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors
Open accessAbstract
We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide 56 (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clinical trials. This compound displays excellent PARP 1 and 2 inhibition with IC(50) = 3.8 and 2.1 nM, respectively, and in a whole cell assay, it inhibited PARP activity with EC(50) = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC(50) in the 10-100 nM range. Compound 56 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer.
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Cited by
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“MRL-45696, kindly provided by Thomas Vogt from Merck Research Laboratories, is closely related to the potent Parib, niraparib, or 2-phenyl-2H-indazole-7-carboxamide (Jones et al., 2009).”
Background
Metadata
- Authors
- Jones, P., Altamura, S., Boueres, J., Ferrigno, F., Fonsi, M., Giomini, C., Lamartina, S., Monteagudo, E., Ontoria, J. M., Orsale, M. V., Palumbi, M. C., Pesci, S., Roscilli, G., Scarpelli, R., Schultz-Fademrecht, C., Toniatti, C., & Rowley, M.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2009-10-29
- Volume
- 52
- Issue
- 22
- Pages
- 7170-7185
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2160399783
- Cited by
- 316
- References
- 37
- FWCI
- 5.22
- Type
- journal article
- Language
- en
- Open access
- green
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