Discovery of N-(2-Aminophenyl)-4-[(4-pyridin-3-ylpyrimidin-2-ylamino) methyl]benzamide(MGCD0103), an orally active histone deacetylase inhibitor

Journal of Medicinal Chemistry

Volumn 51, Issue 14, 2008, Pages 4072-4075

  Zhou, Nancy ^a   Moradei, Oscar ^a   Raeppel, Stephane ^a   Leit, Silvana ^a   Frechette, Sylvie ^a   Gaudette, Frederic ^a   Paquin, Isabelle ^a   Bernstein, Naomy ^a   Bouchain, Giliane ^a   Vaisburg, Arkadii ^a   Jin, Zhiyun ^a   Gillespie, Jeff ^a   Wang, James ^a   Fournel, Marielle ^a   Yan, Pu T ^a   Trachy Bourget, Marie Claude ^a   Kalita, Ann ^a   Lu, Aihua ^a   Rahil, Jubrail ^a   MacLeod, A Robert ^a,b   Li, Zuomei ^a   Besterman, Jeffrey M ^a   Delorme, Daniel ^a,c   more..

^a METHYLGENE INC   (Canada)

^b Takeda San Diego Inc   (United States)

^c Neurochem Inc   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN DEPENDENT KINASE INHIBITOR 1; HISTONE; HISTONE DEACETYLASE 1; HISTONE DEACETYLASE 2; HISTONE DEACETYLASE 3; HISTONE DEACETYLASE INHIBITOR; N (2 AMINOPHENYL) 4 [4 (3 PYRIDINYL) 2 PYRIMIDINYLAMINOMETHYL]BENZAMIDE;

ACETYLATION; ANIMAL EXPERIMENT; ANIMAL MODEL; ANOREXIA; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; AREA UNDER THE CURVE; ARTICLE; CANCER CELL CULTURE; CELL CYCLE ARREST; CELL PROLIFERATION; CLINICAL TRIAL; CONCENTRATION RESPONSE; DIARRHEA; DISTRIBUTION VOLUME; DOG; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG DESIGN; DRUG ELIMINATION; DRUG HALF LIFE; DRUG SCREENING; DRUG SELECTIVITY; DRUG SYNTHESIS; DRUG TOLERABILITY; FATIGUE; FEMALE; GASTROINTESTINAL SYMPTOM; HUMAN; HUMAN CELL; IN VITRO STUDY; IN VIVO STUDY; LEUKEMIA; MOUSE; MYELODYSPLASTIC SYNDROME; NAUSEA; NONHUMAN; PROTEIN EXPRESSION; RAT; SOLID TUMOR; STRUCTURE ACTIVITY RELATION; TUMOR XENOGRAFT; VOMITING;

ADMINISTRATION, ORAL; ANIMALS; BENZAMIDES; DOGS; DRUG SCREENING ASSAYS, ANTITUMOR; ENZYME INHIBITORS; ENZYME-LINKED IMMUNOSORBENT ASSAY; FEMALE; FLOW CYTOMETRY; HISTONE DEACETYLASES; HUMANS; MALE; PYRIMIDINES; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 47749102080     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm800251w     Document Type: Article

References (37)

1. (a) Marks, P. A.; Rifkind, R. A.; Richon, V. M.; Breslow, R.; Miller, T.; Kelly, W. K. Histone deacetylases and cancer: causes and therapies. Nat. Rev. Cancer 2001, 1, 194-202.
2. (b) Hassig, C. A.; Schreiber, S. L. Nuclear histone acetylases and deacetylases and transcriptional regulation: HATs off to HDACs. Curr. Opin. Chem. Biol. 1997, 1, 300-308.
3. (c) Kouzarides, T. Histone acetylases and deacetylases in cell proliferation. Curr. Opin. Genet. Dev. 1999, 9, 40-48.
4. (d) Minucci, S.; Pelicci, G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat. Rev. Cancer 2006, 6, 38-51.
5. (e) Moradei, O.; Maroun, C. R.; Paquin, I.; Vaisburg, A. Histone deacetylase inhibitors: latest developments, trends and prospects. Curr. Med. Chem.: Anti-Cancer Agents 2005, 5, 529-560.
6. Drummond, D. C.; Noble, G. K.; Kirpotin, D. B.; Guo, Z.; Scott, G. K.; Benz, C. C. Clinical development of histone deacetylase inhibitors as anticancer agents. Annu. Rev. Pharmacol. Toxicol. 2005, 45, 495-528.
7. (a) Kim, Y. B.; Lee, K. H.; Sugita, K.; Yoshida, M.; Horinouchi, S. Oxamflatin is a novel antitumor compound that inhibits mammalian histone deacetylase. Oncogene 1999, 18, 2461-2470.
8. (b) Meinke, P. T.; Liberator, P. Histone deacetylase: a target for antiproliferative and antiprotozoal agents. Curr. Med. Chem. 2000, 8, 211-235.
9. (c) Patent Application US 651 1990 B1, 2003.
10. (d) Kelly, W. K.; O'Connor, O. A.; Krug, L. M.; Chiao, J. H.; Heaney, M.; Curley, T.; MacGregore-Cortelli, B.; Tong, W; Secrist, J. P.; Schwartz, L.; Richardson, S.; Chu, E.; Olgac, S.; Marks, P. A.; Scher, H.; Richon, V. M. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J. Clin. Oncol. 2005, 23, 3923-3931.
11. (a) Patent Application WO 2004/092115, 2004.
12. (b) Buggy, J. J.; Cao, Z. A.; Bass, K. E.; Verner, E.; Balasubramanian, S.; Liu, L.; Schultz, B. E.; Young, P. R.; Dalrymple, S. A. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol. Cancer Ther. 2006, 5, 1309-1317.
13. (a) Plumb, J. A.; Finn, P. W.; Williams, R. J.; Bandara, M. J.; Romero, M. R.; Watkins, C. J.; La Tangue, N. B.; Brown, R. Pharmacodynamic response and inhibition of growth of human tumor xenografts by the novel histone deacetylase inhibitor PXD101. Mol. Cancer Ther. 2003, 2, 721-728.
14. (b) Patent Application WO 0230879A2, 2002.
15. (c) Steele, N. L.; Plumb, J. A.; Vidal, L.; Tjørnelund, J.; Knoblauch, P.; Rasmussen, A.; Ooi, C. E.; Buhl-Jensen, P.; Brown, R.; Evans, T. R.; Debono, J. S. A phase 1 pharmacokinetic and pharmacodynamic study of the histone deacetylase inhibitor belinostat in patients with advanced solid tumors. Clin. Cancer Res. 2008, 14, 804-810.
16. Giles, F.; Fischer, T.; Cortes, J.; Garcia-Manero, G.; Beck, J.; Ravandi, F.; Masson, E.; Rae, P.; Laird, G.; Sharma, S.; Kantarjian, H.; Dugan, M.; Albitar, M.; Bhalla, K. A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies. Clin. Cancer Res. 2006, 12, 4628-4635.
17. Fong, P. C.; Settatree, S.; Sinha, R.; Hardcastle, A.; Hellemans, P. W.; Arts, J.; Brown, K. H.; Janicot, M.; Aherne, W.; De Bono, J. S. A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumors. J. Clin. Oncol. 2007, 25, 3578.
18. (a) Saito, A.; Yamashita, T.; Mariko, Y.; Nosaka, Y.; Tsuchiya, K.; Ando, T.; Suzuki, T.; Tsuruo, T.; Nakanishi, O. A synthetic inhibitor of histone deacetylase, MS-275, with marked in vivo antitumor activity against human tumors. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 4592-4597.
19. (b) Suzuki, T.; Ando, T.; Tsuchiya, K.; Fukasawa, N.; Saito, A.; Mariko, Y.; Yamashita, T.; Nakanishi, O. Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J. Med. Chem. 1999, 42, 3001-3003.
20. (c) Patent Application US 6174905 B1, 2001.
21. (d) Ryan, Q. C.; Headlee, D.; Acharya, M.; Sparreboom, A.; Trepel, J. B.; Ye, J.; Figg, W. D.; Hwang, K.; Chung, E. J.; Murgo, A.; Melillo, G.; Elsayed, Y.; Monga, M.; Kalnitskiy, M.; Zwiebel, J.; Sausville, E. A. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J. Clin. Oncol. 2005, 23, 3912-3922.
22. Lavoie, R.; Bouchain, G.; Frechette, S.; Woo, S. H.; Abou-Khalil, E.; Leit, S.; Fournel, M.; Yan, P. T.; Trachy-Bourget, M.-C.; Beaulieu, C.; Li, Z.; Besterman, J.; Delorme, D. Design and synthesis of a novel class of histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2001, 11, 2847-2850.
23. Bouchain, G.; Leit, S.; Frechette, S.; Abou-Khalil, E.; Lavoie, R.; Moradei, O.; Woo, S.-H.; Fournel, M.; Yan, P. T.; Kalita, A.; Trachy-Bourget, M.-C.; Beaulieu, C.; Li, Z; Robert, M.-F.; MacLeod, A. R.; Besterman, J. M.; Delorme, D. Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J. Med. Chem. 2003, 46, 820-830.
24. Woo, S. H.; Frechette, S.; Abou-Khalil, E.; Bouchain, G.; Vaisburg, A.; Bernstein, N.; Moradei, O.; Leit, S.; Allan, M.; Fournel, M.; Trachy-Bourget, M.-C; Li, Z.; Besterman, J.; Delorme, D. Structurally simple trichostatin A-like straight chain hydroxamates as potent histone deacetylase inhibitors. J. Med. Chem. 2002, 45, 2877-2885.
25. Vaisburg, A.; Bernstein, N.; Frechette, S.; Allan, M.; Abou-Khalil, E.; Leit, S.; Moradei, O.; Bouchain, G.; Wang, J.; Woo, S. H.; Fournel, M.; Yan, P. T.; Trachy-Bourget, M.-C.; Kalita, A.; Beaulieu, C.; Li, Z.; MacLeod, R.; Besterman, J. M.; Delorme, D. (2-Amino-phenyl)-amides of omega-substituted alkanoic acids as new histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 283-287.
26. Patent Application WO 2004/035525, 2004.
27. (a) Patent Application WO 2003/024448, 2003.
28. (b) Moradei, O.; Leit, S.; Zhou, N.; Frechette, S.; Paquin, I.; Raeppel, S.; Gaudette, F.; Bouchain, G.; Woo, S.; Vaisburg, A.; Fournel, M.; Kalita, A.; Lu, A.; Trachy-Bourget, M.; Yan, P.; Liu, J.; Li, Z.; Rahil, J.,; MacLeod, A.; Besterman, J.; Delorme, D. Substituted N-(2-aminophenyl)-benzamides, (E)-N-(2-aminophenyl)-acrylamides and their analogues: novel classes of histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 4048-4052.
29. (a) Paquin, I.; Raeppel, S.; Leit, S.; Gaudette, F.; Zhou, N.; Moradei, O.; Saavedra, O.; Bernstein, N.; Raeppel, F.; Bouchain, G.; Fréchette, S.; Woo, S.; Vaisburg, A.; Fournel, M.; Kalita, A.; Robert, M-F.; Lu, A.; Trachy-Bourget, M.; Yan, P.; Liu, J.; Rahil, J.; MacLeod, A.; Besterman, J.; Li, Z.; Delorme, D. Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]- N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 1067-1071.
30. (b) Fréchette, S.; Leit, S.; Woo, S. H.; Lapointe, G.; Jeannotte, G.; Moradei, O.; Paquin, I.; Bouchain, G.; Raeppel, S.; Gaudette, F.; Zhou, N.; Vaisburg, A.; Fournel, M.; Yan, P.; Trachy-Bourget, M.; Kalita, A.; Robert, M.-F.; Lu, A.; Rahil, J.; MacLeod, A.; Besterman, J.; Li, Z.; Delorme, D. 4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors. Bioorg. Med. Chem. Lett. 2008, 18, 1502-1506.
31. Patent Application WO 2005/092899, 2005.
32. (a) Patent Application WO 2005/030704, 2005.
33. (b) Patent Application WO 2005/030705, 2005.
34. U.S. Patent 6,897,220, 2005.
35. Garcia-Manero, G.; Minden, M.; Estrov, E.; Verstovsek, S.; Newsome, W.; Reid, G.; Besterman, J.; Li, Z.; Pearce, L.; Martell, R. Clinical activity and safety of the histone deacetylase inhibitor MGCD0103: results of a phase I study in patients with leukemia or myelodysplastic syndromes (MDS). J. Clin. Oncol. 2006, 24 (18, Suppl.), 6500.
36. Carducci, M.; Siu, L. L.; Sullivans, R.; Maclean, M.; Kalita, A.; Chen, E. X.; Pili, R.; Martell, R. E.; Besterman, J.; Reid, G. Phase I study of isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 given as three-times weekly oral dose in patients (pts) with advanced solid tumors. J. Clin. Oncol. 2006, 24 (18, Suppl.), 3007.
37. Fournel, M.; Bonfils, C.; Hou, Y.; Yan, T.; Trachy-Bourget, M.-C.; Kalita, A.; Liu, J.; Lu, A.-H.; Zhou, N. Z.; Robert, M.-F.; Gillespie, J.; Wang, J. J.; Ste-Croix, H.; Rahil, J.; Lefebvre, S.; Moradei, O.; Delorme, D.; MacLeod, A. R.; Besterman, J. M.; Li, Z. MGCD0103, a novel isotype-selective histone deacetylase inhibitor, has broad spectrum antitumor activity in vitro and in vivo. Mol. Cancer Ther. 2008, 7 (4), 759-768.