Design and synthesis of novel N-hydroxy-dihydronaphthyridinones as potent and orally bioavailable HIV-1 integrase inhibitors

Journal of Medicinal Chemistry

Volumn 54, Issue 9, 2011, Pages 3393-3417

  Johnson, Ted W ^a   Tanis, Steven P ^a   Butler, Scott L ^a   Dalvie, Deepak ^a   Delisle, Dorothy M ^a   Dress, Klaus R ^a   Flahive, Erik J ^a   Hu, Qiyue ^a   Kuehler, Jon E ^a   Kuki, Atsuo ^a   Liu, Wen ^a   McClellan, Guy A ^a   Peng, Qinghai ^a   Plewe, Michael B ^a   Richardson, Paul F ^a   Smith, Graham L ^a   Solowiej, Jim ^a   Tran, Khanh T ^a   Wang, Hai ^a   Yu, Xiaoming ^a   Zhang, Junhu ^a   Zhu, Huichun ^a   more..

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 [(3,3 DIFLUOROPYRROLIDIN 1 YL)METHYL] 3 (4 FLUOROBENZYL) 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 1 [(3,3 DIFLUOROPYRROLIDIN 1 YL)METHYL] 3 (4 FLUOROBENZYL) 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C] 1,7 NAPHTHYRIDIN 6 ONE; 1 [(DIMETHYLAMINO)METHYL] 3 (4 FLUOROBENZYL) 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C] 1,7 NAPHTHYRIDIN 6 ONE; 1 [[(2 METHOXYETHYL)(METHYL)AMINO]METHYL] 3 (4 FLUOROBENZYL) 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 1 [[(2 METHOXYETHYL)(METHYL)AMINO]METHYL] 3 (4 FLUOROBENZYL) 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 1 [[(CYCLOPROPYLMETHYL)(METHYL)AMINO]METHYL] 3 (4 FLUOROBENZYL) 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 1 [[(CYCLOPROPYLMETHYL)(METHYL)AMINO]METHYL] 3 (4 FLUOROBENZYL) 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 (4 FLUOROBENZYL) 1 (PIPERIDIN 1 YLMETHYL) 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 (4 FLUOROBENZYL) 1 [(DIMETHYLAMINO)METHYL] 7 [[2 (TRIMETHYLSILYL)ETHOXY)METHOXY] 8,9 DIHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6(7H) ONE; 3 (4 FLUOROBENZYL) 1 BROMO 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 8,9 DIHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6(7H) ONE; 3 (4 FLUOROBENZYL) 1 IODO 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 (4 FLUOROBENZYL) 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 8,9 DIHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6(7H) ONE; 3 (4 FLUOROBENZYL) 7 HYDROXY 1 (PIPERIDIN 1 YLMETHYL) 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C] 1,7 NAPHTHYRIDIN 6 ONE; 3 (4 FLUOROBENZYL) 7 HYDROXY 1 [[(2 HYDROXYETHYL)(METHYL)AMINO]METHYL] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C] 1,7 NAPHTHYRIDIN 6 ONE; 3 (4 FLUOROBENZYL) 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(3,5 DIFLUOROPYRIDIN 2 YL)METHYL] 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(3,5 DIFLUOROPYRIDIN 2 YL)METHYL] 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(4 FLUOROPHENYL)METHYL] 3,7,8,9 TETRAHYDRO 7 [(TETRAHYDRO 2H PYRAN 2 YL)OXY] 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(4 FLUOROPHENYL)METHYL] 3,7,8,9 TETRAHYDRO 7 HYDROXY 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(5 FLUOROPYRIDIN 2 YL)METHYL] 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 3 [(5 FLUOROPYRIDIN 2 YL)METHYL] 7 HYDROXY 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; 5 FLUORO 2 [(7 HYDROXY 6 OXO 6,7,8,9 TETRAHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 3 YL)METHYL]BENZONITRILE; 5 FLUORO 2 [[6 OXO 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 6,7,8,9 TETRAHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 3 YL]METHYL]BENZONITRILE; 5 FLUORO 6 CHLORO 2 [(7 HYDROXY 6 OXO 6,7,8,9 TETRAHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 3 YL)METHYL]BENZONITRILE; 5 FLUORO 6 CHLORO 2 [[6 OXO 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 6,7,8,9 TETRAHYDRO 3H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 3 YL]METHYL]BENZONITRILE; 7 [[2 (TRIMETHYLSILYL)ETHOXY]METHOXY] 3,7,8,9 TETRAHYDRO 6H PYRROLO[2,3 C][1,7]NAPHTHYRIDIN 6 ONE; ANTIVIRUS AGENT; INTEGRASE INHIBITOR; N HYDROXYDIHYDRONAPHTHYRIDINONE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANTIVIRAL ACTIVITY; ARTICLE; DOG; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; ENZYME ACTIVITY; HUMAN IMMUNODEFICIENCY VIRUS 1; IN VITRO STUDY; IN VIVO STUDY; LIPOPHILICITY; METAL BINDING; NONHUMAN;

ADMINISTRATION, ORAL; ANIMALS; BIOLOGICAL AVAILABILITY; CELL MEMBRANE PERMEABILITY; CELLS, CULTURED; DOGS; DRUG DESIGN; HEPATOCYTES; HETEROCYCLIC COMPOUNDS, 3-RING; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; LIVER; MOLECULAR CONFORMATION; NAPHTHYRIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 79955847265     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200208d     Document Type: Article

References (43)

1. Castro, H. C.; Loureiro, N. I.; Pujol-Luz, M.; Souza, A. M.; Albuquerque, M. G.; Santos, D. O.; Cabral, L. M.; Frugulhetti, I. C.; Rodrigues, C. R. HIV-1 reverse transcriptase: a therapeutical target in the spotlight Curr. Med. Chem. 2006, 13 (3) 313-324
2. Mastrolorenzo, A.; Rusconi, S.; Scozzafava, A.; Barbaro, G.; Supuran, C. T. Inhibitors of HIV-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors Curr. Med. Chem. 2007, 14 (26) 2734-2748 (Pubitemid 350130917)
3. Al-Mawsawi, L. Q.; Al-Safi, R. I.; Neamati, N. Anti-infectives: clinical progress of HIV-1 integrase inhibitors Expert Opin. Emerging Drugs 2008, 13 (2) 213-225 (Pubitemid 351958439)
4. Pace, P.; Rowley, M. Integrase inhibitors for the treatment of HIV infection Curr. Opin. Drug Discovery Dev. 2008, 11 (4) 471-479 (Pubitemid 351950842)
5. Anker, M.; Corales, R. B. Raltegravir (MK-0518): a novel integrase inhibitor for the treatment of HIV infection Expert Opin. Invest. Drug. 2008, 17 (1) 97-103 (Pubitemid 351578214)
6. Summa, V.; Petrocchi, A.; Bonelli, F.; Crescenzi, B.; Donghi, M.; Ferrara, M.; Fiore, F.; Gardelli, C.; Gonzalez Paz, O.; Hazuda, D. J.; Jones, P.; Kinzel, O.; Laufer, R.; Monteagudo, E.; Muraglia, E.; Nizi, E.; Orvieto, F.; Pace, P.; Pescatore, G.; Scarpelli, R.; Stillmock, K.; Witmer, M. V.; Rowley, M. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection J. Med. Chem. 2008, 51 (18) 5843-5855
7. Shimura, K.; Kodama, E.; Sakagami, Y.; Matsuzaki, Y.; Watanabe, W.; Yamataka, K.; Watanabe, Y.; Ohata, Y.; Doi, S.; Sato, M.; Kano, M.; Ikeda, S.; Matsuoka, M. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137) J. Virol. 2008, 82 (2) 764-774
8. Min, S.; Song, I.; Borland, J.; Chen, S.; Lou, Y.; Fujiwara, T.; Piscitelli, S. C. Pharmacokinetics and safety of S/GSK1349572, a next-generation HIV integrase inhibitor, in healthy volunteers Antimicrob. Agents Chemother. 2010, 54 (1) 254-258
9. Sato, A.; Kobayashi, M.; Yoshinaga, T.; Fujiwara, T.; Underwood, M.; Johns, B.; Foster, S.; Hazen, R.; Ferris, R.; Brown, K.; Garvey, E. S/GSK1349572 is a Potent Next Generation HIV Integrase Inhibitor. In Fifth IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Cape Town, South Africa, July 19-22, 2009.
10. Johns, B.; Kawasuji, T.; Taishi, T.; Yoshida, H.; Garvey, E.; Spreen, W.; Underwood, M.; Sato, A.; Yoshinaga, T.; Fujiwara, T., The Discovery of S/GSK1349572: A Once-Daily Next Generation Integrase Inhibitor with a Superior Resistance Profile. In 17th Conference on Retroviruses and Opportunistic Infections, San Francisco, 2010.
11. Serrao, E.; Odde, S.; Ramkumar, K.; Neamati, N. Raltegravir, elvitegravir, and metoogravir: the birth of me-too HIV-1 integrase inhibitors Retrovirology 2009, 6, 25
12. Plewe, M. B.; Butler, S. L.; Dress, K. R.; Hu, Q.; Johnson, T. W.; Kuehler, J. E.; Kuki, A.; Lam, H.; Liu, W.; Nowlin, D.; Peng, Q.; Rahavendran, S. V.; Tanis, S. P.; Tran, K. T.; Wang, H.; Yang, A.; Zhang, J. Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors J. Med. Chem. 2009, 52 (22) 7211-7219
13. Tanis, S. P.; Plewe, M. B.; Johnson, T. W.; Butler, S. L.; Davie, D.; Yu, X.; Delisle, D.; Dress, K. R.; Hu, Q.; Huang, B.; Kuehler, J. E.; Kuki, A.; Liu, W.; Peng, Q.; Smith, G. L.; Solowiej, J.; Tran, K. T.; Wang, H.; Yang, A.; Yin, C.; Zhang, J.; Zhu, H. Azaindole N -Methyl Hydroxamic Acids as HIV-1 Integrase Inhibitors-II. The Impact of Physicochemical Properties on ADME and PK Bioorg. Med. Chem. Lett. 2010, 20, 7429
14. Hazuda, D. J.; Felock, P. J.; Hastings, J. C.; Pramanik, B.; Wolfe, A. L. Differential divalent cation requirements uncouple the assembly and catalytic reactions of human immunodeficiency virus type 1 integrase J. Virol. 1997, 71 (9) 7005-7011 (Pubitemid 27355366)
15. Konsavage, W. M., Jr.; Sudol, M.; Katzman, M. Effects of varying the spacing within the D,D-35-E motif in the catalytic region of retroviral integrase Virology 2008, 379 (2) 223-233
16. Bacchi, A.; Biemmi, M.; Carcelli, M.; Carta, F.; Compari, C.; Fisicaro, E.; Rogolino, D.; Sechi, M.; Sippel, M.; Sotriffer, C. A.; Sanchez, T. W.; Neamati, N. From ligand to complexes. Part 2. Remarks on human immunodeficiency virus type 1 integrase inhibition by beta-diketo acid metal complexes J. Med. Chem. 2008, 51 (22) 7253-7264
17. Sechi, M.; Bacchi, A.; Carcelli, M.; Compari, C.; Duce, E.; Fisicaro, E.; Rogolino, D.; Gates, P.; Derudas, M.; Al-Mawsawi, L. Q.; Neamati, N. From ligand to complexes: inhibition of human immunodeficiency virus type 1 integrase by beta-diketo acid metal complexes J. Med. Chem. 2006, 49 (14) 4248-4260 (Pubitemid 44036668)
18. Calculations were performed with Jaguar 7.7, Schrodinger, LLC, Portland, Oregon, 2010. A conformational search was first performed using the OPLS2005 force field in water with Mixed torsional/Low-mode sampling method. This resulted in total four representative conformers, global-min a and conf1-conf3 b-d. Further geometry optimization of those four conformers are performed in Jaguar using ab initio calculations with basis set of B3LYP/6-31G* and PBF solvation model in water. No imaginary frequencies were found for any of the four conformations. The final single point energies were obtained at B3LYP/ CC-PVTZ(-F)++ level with PBF solvation model in water. Conf4 e was derived by twisting the two torsion angles to the presumed binding orientation with the pyridine nitrogen, the carbonyl, and the hydroxamate oxygen all coplanar based on the global-min conformation from above and performing constrained minimization of the rest of the structure using basis set of B3LYP/6-31G* and PBF solvation model in water. One imaginary frequency was found at -96.684. The final single point energies were obtained at B3LYP/ CC-PVTZ(-F)++ level with PBF solvation model in water.
19. Echavarren, A. M.; Stille, J. K. Palladium-catalyzed coupling of aryl triflates with organostannanes J. Am. Chem. Soc. 1987, 109, 5478-5486
20. Wollenberg, R. H.; Albizati, K. F.; Peries, R. A nucleophilic acetaldehyde equivalent. Preparation and synthetic applications of cis-2-ethoxyvynillithium J. Am. Chem. Soc. 1977, 99, 7365-7367
21. Littke, A. F.; Fu, G. C. A versatile catalyst for Heck reactions of aryl chlorides and aryl bromides under mild conditions J. Am. Chem. Soc. 2001, 123 (29) 6989-7000 (Pubitemid 32884168)
22. Ullrich, T.; Krich, S.; Binder, D.; Mereiter, K.; Anderson, D. J.; Meyer, M. D.; Pyerin, M. Conformationally constrained nicotines: polycyclic, bridged, and spiro-annulated analogues as novel ligands for the nicotinic acetylcholine receptor J. Med. Chem. 2002, 45 (18) 4047-4054 (Pubitemid 35024306)
23. Masaguer, C. F.; Ravina, E.; Fueyo, J. Alkylation of 3-ehtyl-2-methyl-4- oxo-4,5,6,7-tetrahydroindole with bromoesters: benzene sulfonyl as a convenient nitrogen protecting group Heterocycles 1992, 34, 1303-1309
24. Kozikowski, A. P.; Ishida, H. Use of N, N -dimethyl(methylene)ammonium chloride inthe functionalization of indoles Heterocycles 1980, 14, 55-58
25. Kashdan, D. S.; Schwartz, J. A.; Rapaport, H. Synthesis of 1,2,3,4-tetrahydroisoquinolines J. Org. Chem. 2008, 47, 2638-2643
26. Schnute, M. E.; Brideau, R. J.; Collier, S. A.; Cudahy, M. M.; Hopkins, T. A.; Knechtel, M. L.; Oien, N. L.; Sackett, R. S.; Scott, A.; Stephan, M. L.; Wathen, M. W.; Wieber, J. L. Synthesis of 4-oxo-4,7-dihydrofuro[2,3- b ]pyridine-5-carboxamides with broad-spectrum human herpesvirus polymerase inhibition Bioorg. Med. Chem. Lett. 2008, 18, 3856-3859
27. Zhao, Z.; Wolkenberg, S. E.; Sanderson, P. E.; Lu, M.; Munshi, V.; Moyer, G.; Feng, M.; Carella, A. V.; Ecto, L. T.; Gabryelski, L. J.; Lai, M. T.; Prasad, S. G.; Yan, Y.; McGaughey, G. B.; Miller, M. D.; Lindsley, C. W.; Hartman, G. D.; Vacca, J. P.; Williams, T. M. Novel indole-3-sulfonamides as potent HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs) Bioorg. Med. Chem. Lett. 2008, 18 (2) 554-559
28. Ryckmans, T.; Edwards, M. P.; Horne, V. A.; Correia, A. M.; Owen, D. R.; Thompson, L. R.; Tran, I.; Tutt, M. F.; Young, T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis Bioorg. Med. Chem. Lett. 2009, 19 (15) 4406-4409
29. Antonio, L.; Grillasca, J. P.; Taskinen, J.; Elovaara, E.; Burchell, B.; Piet, M. H.; Ethell, B.; Ouzzine, M.; Fournel-Gigleux, S.; Magdalou, J. Characterization of catechol glucuronidation in rat liver Drug Metab. Dispos. 2002, 30 (2) 199-207 (Pubitemid 34106540)
30. Ouzzine, M.; Barre, L.; Netter, P.; Magdalou, J.; Fournel-Gigleux, S. The human UDP-glucuronosyltransferases: structural aspects and drug glucuronidation Drug Metab. Rev. 2003, 35 (4) 287-303 (Pubitemid 38018108)
31. Exner, O.; Hradil, M.; Mollin, J. Dissociation of Hydroxamic Acids Collect. Czech. Chem. Commun. 1993, 58, 1109-1121
32. Johnson, T. W.; Dress, K. R.; Edwards, M. Using the Golden Triangle to optimize clearance and oral absorption Bioorg. Med. Chem. Lett. 2009, 19 (19) 5560-5564
33. Skiles, G. L.; Yost, G. S. Mechanistic studies on the cytochrome P450-catalyzed dehydrogenation of 3-methylindole Chem. Res. Toxicol. 1996, 9 (1) 291-297
34. Baranczewski, P.; Stanczak, A.; Kautiainen, A.; Sandin, P.; Edlund, P. O. Introduction to early in vitro identification of metabolites of new chemical entities in drug discovery and development Pharmacol. Rep. 2006, 58 (3) 341-352 (Pubitemid 44111069)
35. Flipo, M.; Charton, J.; Hocine, A.; Dassonneville, S.; Deprez, B.; Deprez-Poulain, R. Hydroxamates: relationships between structure and plasma stability J. Med. Chem. 2009, 52 (21) 6790-6802
36. Summers, J. B.; Mazdiyasni, H.; Holms, J. H.; Ratajczyk, J. D.; Dyer, R. D.; Carter, G. W. Hydroxamic acid inhibitors of 5-lipoxygenase J. Med. Chem. 1987, 30 (3) 574-80 (Pubitemid 17033667)
37. 90 (6 nM). Free fraction in 100% human plasma is 24%.
38. ?-DNA polymerase, β-DNA polymerase, α-DNA polymerase, carbonic anhydrase, matrix metalloproteinase (MMP-1, 2, 3, 7, 8, 9, 13), all show 0% inhbition at 10 uM.
39. Weislow, O. S.; Kiser, R.; Fine, D. L.; Bader, J.; Shoemaker, R. H.; Boyd, M. R. New soluble-formazan assay for HIV-1 cytopathic effects: application to high-flux screening of synthetic and natural products for AIDS-antiviral activity J. Natl. Cancer Inst. 1989, 81 (8) 577-586 (Pubitemid 19104488)
40. Hu, Q.; Kuki, A.; Nowlin, D. M.; Plewe, M. B.; Wang, H.; Zhang, J. HIV Integrase Inhibitors, Pharmceutical Compositions and Methods for their Use. U.S. Patent 7,368,571, May 6, 2008.
41. Chen, J. C.; Krucinski, J.; Miercke, L. J.; Finer-Moore, J. S.; Tang, A. H.; Leavitt, A. D.; Stroud, R. M. Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding Proc. Natl. Acad. Sci. U.S.A. 2000, 97 (15) 8233-8238 (Pubitemid 30639655)
42. Wee, A. G. H.; Shu, A. Y. L.; Bunnenberg, E.; Djerassi, C. Magnetic circular dichroism studies. 66. Synthesis of demethyl monosubstituted porphyrins. The effect of substituent conformation on the magnetic circular dichroism spectra of ethoxycarbonyl porphyrins J. Org. Chem. 1984, 49, 3327-3336
43. Ginzel, K.-D.; Brungs, P.; Steckhan, E. Indirect electrochemical α-methoxylation of N -acyl and N -carboalkoxy α-amino acid esters and application as cationic glycine equivalents Tetrahedron 1989, 45, 1691-1701