Discovery of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A novel oral poly(ADP-ribose)polymerase (PARP) inhibitor efficacious in BRCA-1 and -2 mutant tumors

Journal of Medicinal Chemistry

Volumn 52, Issue 22, 2009, Pages 7170-7185

  Jones, Philip ^a   Altamura, Sergio ^a   Boueres, Julia ^a   Ferrigno, Federica ^a   Fonsi, Massimiliano ^a   Giomini, Claudia ^a   Lamartina, Stefania ^a   Monteagudo, Edith ^a   Ontoria, Jesus M ^a   Orsale, Maria Vittoria ^a   Palumbi, Maria Cecilia ^a   Pesci, Silvia ^a   Roscilli, Giuseppe ^a   Scarpelli, Rita ^a   Schultz Fademrecht, Carsten ^a   Toniatti, Carlo ^a   Rowley, Michael ^a  

^a IRBM   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

1 [4 [7 (AMINOCARBONYL) 2H INDAZOL 2 YL]PHENYL] N METHYLETHANAMINIUM CHLORIDE; 2 [4 (1 HYDROXY 1 METHYLETHYL)PHENYL] 2H INDAZOLE 7 CARBOXAMIDE; 2 [4 (PIPERIDIN 3 YL)PHENYL] 2H INDAZOLE 7 CARBOXAMIDE; 2 [4 [7 (AMINOCARBONYL) 2H INDAZOL 2 YL]PHENYL] N METHYLPROPAN 2 AMINIUM TRIFLUOROACETATE; 2 PHENYL 2H 1,2,3 BENZOTRIAZOLE 4 CARBOXAMIDE; 2 PHENYL 2H INDAZOLE 7 CARBOXAMIDE; 2 PHENYL[1,2,4]TRIAZOLO[1,5 A]PYRIDINE 8 CARBOXAMIDE; 2 PHENYLPYRAZOLO[1,5 A]PYRIDINE 7 CARBOXAMIDE; 3 [4 [7 (AMINOCARBONYL) 2H INDAZOL 2 YL]PHENYL]PIPERIDINIUM CHLORIDE; [4 [7 (AMINOCARBONYL) 2H INDAZOL 2 YL]PHENYL] N METHYLMETHANAMINIUM CHLORIDE; ANTINEOPLASTIC AGENT; BRCA1 PROTEIN; BRCA2 PROTEIN; CYTOCHROME P450 1A1; CYTOCHROME P450 1A2; MK 4827; MUTANT PROTEIN; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 2; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE INHIBITOR; TERT BUTYL 3 [4 [7 (AMINOCARBONYL) 2H INDAZOL 2 YL]PHENYL] PIPERIDINE 1 CARBOXYLATE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; BREAST CANCER; CANCER CELL; CANCER INHIBITION; CELL ACTIVITY; CELL ASSAY; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG IDENTIFICATION; DRUG SELECTIVITY; DRUG SYNTHESIS; ENZYME ACTIVITY; ENZYME INHIBITION; FEMALE; HUMAN; HUMAN CELL; IC 50; IN VIVO STUDY; MOUSE; NONHUMAN; OXIDATION; TUMOR XENOGRAFT; WHOLE CELL;

ADMINISTRATION, ORAL; AMIDES; ANIMALS; CELL LINE, TUMOR; CELL PROLIFERATION; CELL TRANSFORMATION, NEOPLASTIC; DRUG DISCOVERY; DRUG STABILITY; ENZYME INHIBITORS; FEMALE; GENES, BRCA1; GENES, BRCA2; HUMANS; INDAZOLES; INHIBITORY CONCENTRATION 50; MUTATION; NEOPLASMS; PIPERIDINES; POLY(ADP-RIBOSE) POLYMERASES; RATS;

EID: 70949086814     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm901188v     Document Type: Article

References (45)

1. (a) Hassa, P. O.; Hottiger, M. O. The diverse biological roles of mammalian PARPS, a small but powerful family of poly-ADP-ribose polymerases. Front. Biosci. 2008, 13, 3046-3082.
2. (b) Amé, J.-C.; Spenlehauer, C.; de Murcia, G. The PARP superfamily. BioEssays 2004, 26, 882-893.
3. (c) Kleine, H.; Poreba, E.; Lesniewicz, K.; Hassa, P. O.; Hottiger, M. O.; Litchfield, D. W.; Shilton, B. H.; Lüscher, B. Substrate-assisted catalysis by PARP10 limits its activity to mono-ADP-ribosylation. Mol. Cell 2008, 32, 57-69.
4. Jagtap, P.; Szabó, C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat. Rev. Drug Discovery 2005, 4, 421-440.
5. Schreiber, V.; Dantzer, F.; Amé, J.-C.; de Murcia, G. Poly(ADP-ribose): novel functions for an old molecule. Nat. Rev. Mol. Cell Biol. 2006, 7, 517-528.
6. Huber, A.; Bai, P.; de Murcia, J. M.; de Murcia, G. PARP-1, PARP-2 and ATM in the DNA damage response: functional synergy in mouse development. DNA Repair 2004, 3, 1103-1108.
7. n participates in DNA excision repair. Nature (London) 1980, 283, 593-596.
8. de Murcia, J. M.; Niedergang, C.; Trucco, C.; Ricoul, M.; Dutrillaux, B.; Mark, M.; Oliver, F. J.; Masson, M.; Dierich, A.; LeMeur, M.; Walztinger, C.; Chambon, P.; de Murcia, G. Requirement of poly(ADP-ribose) polymerase in recovery from DNA damage in mice and in cells. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 7303-7307.
9. Wang, Z.-Q.; Auer, B.; Stingl, L.; Berghammer, H.; Haidacher, D.; Schweiger, M.; Wagner, E. F. Mice lacking ADPRT and poly-(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev. 1995, 9, 509-520.
10. Tentori, L.; Graziani, G. Chemopotentiation by PARP inhibitors in cancer therapy. Pharmacol. Res. 2005, 52, 25-33.
11. Rodon, J.; Iniesta, M. D.; Papadopoulos, K. Development of PARP inhibitors in oncology. Expert Opin. Invest. Drugs 2009, 18, 31-43.
12. Ratnam, K.; Low, J. A. Current development of clinical inhibitors of poly(ADP-ribose) polymerase in oncology. Clin. Cancer Res. 2007, 13, 1383-1388.
13. (a) Peukert, S.; Schwahn, U. New inhibitors of poly(ADP-ribose) polymerase (PARP). Expert Opin. Ther. Pat. 2004, 14, 1531-1551.
14. (b) Alarcon de la Lastra, C.; Villegas, I.; Sanchez-Fidalgo, S. Poly(ADP-ribose) polymerase inhibitors: new pharmacological functions and potential clinical implications. Curr. Pharm. Des. 2007, 13, 933-962.
15. Moroni, F. Poly(ADP-ribose)polymerase 1 (PARP-1) and postischemic brain damage. Curr. Opin. Pharmacol. 2008, 8, 96-103.
16. Szabó, C. Cardioprotective effects of poly(ADP-ribose) polymerase inhibition. Pharmacol. Res. 2005, 52, 34-43.
17. Cuzzocrea, S. Shock, inflammation and PARP. Pharmacol. Res. 2005, 52, 72-82.
18. Pacher, P.; Szabó, C. Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors. Cardiovasc. Drug Rev. 2007, 25, 235-260.
19. Kauppinen, T. M.; Swanson, R. A. The role of poly(ADP-ribose) polymerase-1 in CNS disease. Neuroscience (Amsterdam) 2007, 145, 1267-1272.
20. Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature (London) 2005, 434, 913-917. (Pubitemid 40559005)
21. Farmer, H.; McCabe, N.; Lord, C. J.; Tutt, A. N. J.; Johnson, D. A.; Richardson, T. B.; Santarosa, M.; Dillon, K. J.; Hickson, I.; Knights, C.; Martin, N. M. B.; Jackson, S. P.; Smith, G. C. M.; Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature (London) 2005, 434, 917-921. (Pubitemid 40559006)
22. McCabe, N.; Turner, N. C.; Lord, C. J.; Kluzek, K.; Bialkowska, A.; Swift, S.; Giavara, S.; O'Connor, M. J.; Tutt, A. N.; Zdzienicka, M. Z.; Smith, G. C. M.; Ashworth, A. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res. 2006, 66, 8109-8115. (Pubitemid 44299177)
23. (a) Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 2002, 108, 171-182. (Pubitemid 34161138)
24. (b) Narod, S. A.; Foulkes, W. D. BRCA1 and BRCA2: 1994 and beyond. Nat. Rev. Cancer 2004, 4, 665-676.
25. Menear, K. A.; Adcock, C.; Boulter, R.; Cockcroft, X.-L.; Copsey, L.; Cranston, A.; Dillon, K. J.; Drzewiecki, J.; Garman, S.; Gomez, S.; Javaid, H.; Kerrigan, F.; Knights, C.; Lau, A.; Loh, V. M., Jr.; Matthews, I. T. W.; Moore, S.; O'Connor, M. J.; Smith, G. C. M.; Martin, N. M. B. 4-[3-(4- Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J. Med. Chem. 2008, 51, 6581-6591.
26. Rottenberg, S.; Jaspers, J. E.; Kersbergen, A.; van der Burg, E.; Nygren, A. O. H.; Zander, S. A. L.; Derksen, P. W. B.; de Bruin, M.; Zevenhoven, J.; Lau, A.; Boulter, R.; Cranston, A.; O'Connor, M. J.; Martin, N. M. B.; Borst, P.; Jonkers, J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 17079-17084.
27. Fong, P. C.; Boss, D. S.; Yap, T. A.; Tutt, A.; Wu, P.; Mergui-Roelvink, M.; Mortimer, P.; Swaisland, H.; Lau, A.; O'Connor, M. J.; Ashworth, A.; Carmichael, J.; Kaye, S. B.; Schellens, J. H. M.; de Bono, J. S. Inhibition of poly(ADP-ribose)polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 2009, 361, 123-134.
28. (a) Penning, T. D.; Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Liu, X.; Shi, Y.; Klinghofer, V.; Johnson, E. F.; Donawho, C. K.; Frost, D. J.; Bontcheva-Diaz, V.; Bouska, J. J.; Osterling, D. J.; Olson, A. M.; Marsh, K. C.; Luo, Y.; Giranda, V. L. Discovery of the poly(ADP-ribose) polymerase (PARP) inhibitor 2-[(R)-2-methylpyrrolidin-2-yl]-1H-benzimidazole-4-carboxamide (ABT-888) for the treatment of cancer. J. Med. Chem. 2009, 52, 514-523.
29. (b) Donawho, C. K.; Luo, Y.; Luo, Y.; Penning, T. D.; Bauch, J. L.; Bouska, J. J.; Bontcheva-Diaz, V. D.; Cox, B. F.; DeWeese, T. L.; Dillehay, L. E.; Ferguson, D. C.; Ghoreishi-Haack, N. S.; Grimm, D. R.; Guan, R.; Han, E. K.; Holley-Shanks, R. R.; Hristov, B.; Idler, K. B.; Jarvis, K.; Johnson, E. F.; Kleinberg, L. R.; Klinghofer, V.; Lasko, L. M.; Liu, X.; Marsh, K. C.; McGonigal, T. P.; Meulbroek, J. A.; Olson, A. M.; Palma, J. P.; Rodriguez, L. E.; Shi, Y.; Stavropoulos, J. A.; Tsurutani, A. C.; Zhu, G.-D.; Rosenberg, S. H.; Giranda, V. L.; Frost, D. J. ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin. Cancer Res. 2007, 13, 2728-2737.
30. Thomas, H. D.; Calabrese, C. R.; Batey, M. A.; Canan, S.; Hostomsky, Z.; Kyle, S.; Maegley, K. A.; Newell, D. R.; Skalitzky, D.; Wang, L.-Z.; Webber, S. E.; Curtin, N. J. Preclinical selection of a novel poly(ADP-ribose) polymerase inhibitor for clinical trial. Mol. Cancer Ther. 2007, 6, 945-956.
31. Mason, K. A.; Valdecanas, D.; Hunter, N. R.; Milas, L. INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin. Invest. New Drugs 2008, 26, 1-5.
32. Kopetz, S.; Mita, M. M.; Mok, I.; Sankhala, K. K.; Moseley, J.; Sherman, B. M.; Bradley, C. R.; Tolcher, A. W. First in Human Phase I Study of BSI-201, a Small Molecule Inhibitor of Poly ADP-ribose Polymerase (PARP) in Subjects with Advanced Solid Tumors. Presented at the 44th Annual Meeting of the ASCO, Chicago, IL, May 31-June 3 2008; Abstract 3577. J. Clin. Oncol. 2008, 26 (May 20 Suppl.), 3577.
33. Kuvshinov, A. M.; Gulevskaya, V. I.; Rozhkov, V. V.; Shevelev, S. A. Synthesis of 2-substituted 4,6-dinitro-2H-indazoles from 2,4,6-trinitrotoluene. Synthesis 2000, 10, 1474-1478.
34. Anderson, P. L.; Hasak, J. P.; Kahle, A. D.; Paolella, N. A.; Shapiro, M. J. 1,3-Dipolar addition of pyridine N-imine to acetylenes and the use of carbon-13 NMR in several structural assignments. J. Heterocycl. Chem. 1981, 18, 1149-1152.
35. Hajos, G.; Timari, G.; Messmer, A.; Zagyva, A.; Miskolczi, I.; Schantl, J. G. A new synthesis of the s-triazolo[1,5-a]pyridine ring system. Monatsh. Chem. 1995, 126, 1213-1215.
36. Ritter, J. J.; Kalish, J. α,α-Dimethyl-β-phenethylamine. Org. Synth. 1964, 44, 44.
37. (a) Ruf, A.; Mennissier de Murcia, J.; de Murcia, G.; Schulz, G. E. Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken. Proc. Natl. Acad. Sci. U.S.A 1996, 93, 7481-7485.
38. + binding to poly(ADP-ribose) polymerase as derived from crystal structures and homology modeling. Biochemistry 1998, 37, 3893-3900.
39. 2 in DCM/AcOH for 48 h, followed by reductive amination.
40. Martignoni, M.; Groothuis, G. M. M.; de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol. 2006, 2, 875-894.
41. Harrigan, J. A.; McGarrigle, B. P.; Sutter, T. R.; Olson, J. R. Tissue specific induction of cytochrome P450 (CYP) 1A1 and 1B1 in rat liver and lung following in vitro (tissue slice) and in vivo exposure to benzo(a)pyrene. Toxicol. in Vitro 2006, 20, 426-438.
42. Ma, Q.; Lu, A. Y. H. CYP1A induction and human risk assessment: an evolving tale of in vitro and in vivo studies. Drug Metab. Dispos. 2007, 35, 1009-1016.
43. Amat, M.; Cantó, M.; Llor, N.; Escolano, C.; Molins, E.; Espinosa, E.; Bosch, J. Dynamic kinetic resolution of racemic γ-aryl-δ- oxoesters. Enantioselective synthesis of 3-arylpiperidines. J. Org. Chem. 2002, 67, 5343-5351.
44. McCabe, N.; Lord, C. J.; Tutt, A. N.; Martin, N. M.; Smith, G. C.; Ashworth, A. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: an issue of potency. Cancer Biol. Ther. 2005, 4, 934-936.
45. MK4827 in Patients with Advanced Solid Tumors and BRCA Mutant Ovarian Cancer. http://clinicaltrial.gov/ct2/show/NCT00749502.