3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H

Journal of Medicinal Chemistry

Volumn 59, Issue 13, 2016, Pages 6136-6148

  Wu, Bulan ^a   Tang, Jing ^a   Wilson, Daniel J ^a   Huber, Andrew D ^b   Casey, Mary C ^b   Ji, Juan ^b   Kankanala, Jayakanth ^a   Xie, Jiashu ^a   Sarafianos, Stefan G ^b   Wang, Zhengqiang ^a  

^a UNIVERSITY OF MINNESOTA   (United States)

^b University of Missouri   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 (TERT BUTYLAMINO) N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; 4 AMINO N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; AMIDE; ANTIVIRUS AGENT; DOLUTEGRAVIR; ESTERASE INHIBITOR; INTEGRASE INHIBITOR; N (2 CHLORO 5 FLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (2,4 DIFLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (2,5 DIFLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3 CHLORO 2 FLUOROBENZYL) 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXO 4 (PROPYLAMINO)PYRIMIDINE 5 CARBOXAMIDE; N (3 CHLORO 2 FLUOROBENZYL) 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 4 (METHYLAMINO) 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3 CHLORO 3 FLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3 FLUOROBENZYL) 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 4 (METHYLAMINO) 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3 FLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3,4 DIFLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (3,5 DIFLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (4 CHLORO 3 FLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (4 FLUOROBENZYL) 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 4 (METHYLAMINO) 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N (4 FLUOROBENZYL) 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXO 4 (BIPHENYLAMINO)PYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXO 4 (PHENYLAMINO)PYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 2,6 DIOXO 4 (PROPYLAMINO)PYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 4 (ISOPROPYLAMINO) 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 1,2,3,6 TETRAHYDRO 4 (METHYLAMINO) 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 4 (CYCLOPROPYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; N BENZYL 1 (HYDROXY) 4 (ETHYLAMINO) 1,2,3,6 TETRAHYDRO 2,6 DIOXOPYRIMIDINE 5 CARBOXAMIDE; PYRIMIDINE DERIVATIVE; RALTEGRAVIR; UNCLASSIFIED DRUG; UNINDEXED DRUG; FUSED HETEROCYCLIC RINGS; INTEGRASE; P31 INTEGRASE PROTEIN, HUMAN IMMUNODEFICIENCY VIRUS 1; PYRIMIDINONE DERIVATIVE; RIBONUCLEASE H;

ANTIVIRAL ACTIVITY; ANTIVIRAL RESISTANCE; ARTICLE; CELL VIABILITY; CONTROLLED STUDY; DRUG DESIGN; DRUG MECHANISM; DRUG POTENCY; DRUG SYNTHESIS; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS 1; IN VITRO STUDY; MOLECULAR MODEL; NONHUMAN; PHYSICAL CHEMISTRY; STRUCTURE ACTIVITY RELATION; ANTAGONISTS AND INHIBITORS; CELL LINE; CHEMISTRY; DRUG EFFECTS; ENZYMOLOGY; HIV INFECTIONS; HUMAN; METABOLISM; PHYSIOLOGY; VIROLOGY;

CELL LINE; DRUG RESISTANCE, VIRAL; HETEROCYCLIC COMPOUNDS, 3-RING; HIV INFECTIONS; HIV INTEGRASE; HIV INTEGRASE INHIBITORS; HIV-1; HUMANS; MODELS, MOLECULAR; PYRIMIDINONES; RALTEGRAVIR POTASSIUM; RIBONUCLEASE H;

EID: 84978676933     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/acs.jmedchem.6b00040     Document Type: Article

References (60)

1. Kinch, M. S.; Patridge, E. An analysis of FDA-approved drugs for infectious disease: HIV/AIDS drugs Drug Discovery Today 2014, 19, 1510-1513 10.1016/j.drudis.2014.05.012
2. Barouch, D. H.; Deeks, S. G. Immunologic strategies for HIV-1 remission and eradication Science 2014, 345, 169-174 10.1126/science.1255512
3. Chun, T. W.; Fauci, A. S. HIV reservoirs: pathogenesis and obstacles to viral eradication and cure AIDS 2012, 26, 1261-1268 10.1097/QAD.0b013e328353f3f1
4. Bagasra, O. A unified concept of HIV latency Expert Opin. Biol. Ther. 2006, 6, 1135-1149 10.1517/14712598.6.11.1135
5. Chun, T.-W.; Stuyver, L.; Mizell, S. B.; Ehler, L. A.; Mican, J. A. M.; Baseler, M.; Lloyd, A. L.; Nowak, M. A.; Fauci, A. S. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy Proc. Natl. Acad. Sci. U. S. A. 1997, 94, 13193-13197 10.1073/pnas.94.24.13193
6. Finzi, D.; Hermankova, M.; Pierson, T.; Carruth, L. M.; Buck, C.; Chaisson, R. E.; Quinn, T. C.; Chadwick, K.; Margolick, J.; Brookmeyer, R.; Gallant, J.; Markowitz, M.; Ho, D. D.; Richman, D. D.; Siliciano, R. F. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy Science 1997, 278, 1295-1300 10.1126/science.278.5341.1295
7. Pommier, Y.; Johnson, A. A.; Marchand, C. Integrase inhibitors to treat HIV/AIDS Nat. Rev. Drug Discovery 2005, 4, 236-248 10.1038/nrd1660
8. Cotelle, P. Patented HIV-1 integrase inhibitors (1998-2005) Recent Pat. Anti-Infect. Drug Discovery 2006, 1, 1-15 10.2174/157489106775244082
9. Henao-Mejia, J.; Goez, Y.; Patino, P.; Rugeles, M. T. Diketo acids derivatives as integrase inhibitors: the war against the acquired immunodeficiency syndrome Recent Pat. Anti-Infect. Drug Discovery 2006, 1, 255-265 10.2174/157489106777452700
10. Dubey, S.; Satyanarayana, Y. D.; Lavania, H. Development of integrase inhibitors for treatment of AIDS: An overview Eur. J. Med. Chem. 2007, 42, 1159-1168 10.1016/j.ejmech.2007.01.024
11. Marchand, C.; Maddali, K.; Metifiot, M.; Pommier, Y. HIV-1 IN inhibitors: 2010 update and perspectives Curr. Top. Med. Chem. 2009, 9, 1016-1037 10.2174/156802609789630910
12. Dayam, R.; Sanchez, T.; Neamati, N. Diketo acid pharmacophore. 2. discovery of structurally diverse inhibitors of HIV-1 integrase J. Med. Chem. 2005, 48, 8009-8015 10.1021/jm050837a
13. Dayam, R.; Sanchez, T.; Clement, O.; Shoemaker, R.; Sei, S.; Neamati, N. b-Diketo acid pharmacophore hypothesis. 1. discovery of a novel class of HIV-1 integrase inhibitors J. Med. Chem. 2005, 48, 111-120 10.1021/jm0496077
14. Deng, J.; Sanchez, T.; Neamati, N.; Briggs, J. M. Dynamic pharmacophore model optimization: identification of novel HIV-1 integrase inhibitors J. Med. Chem. 2006, 49, 1684-1692 10.1021/jm0510629
15. Barreca, M. L.; Ferro, S.; Rao, A.; De Luca, L.; Zappala, M.; Monforte, A.-M.; Debyser, Z.; Witvrouw, M.; Chimirri, A. Pharmacophore-based design of HIV-1 integrase strand-transfer inhibitors J. Med. Chem. 2005, 48, 7084-7088 10.1021/jm050549e
16. Mustata, G. I.; Brigo, A.; Briggs, J. M. HIV-1 integrase pharmacophore model derived from diverse classes of inhibitors Bioorg. Med. Chem. Lett. 2004, 14, 1447-1454 10.1016/j.bmcl.2004.01.027
17. Carlson, H. A.; Masukawa, K. M.; Rubins, K.; Bushman, F. D.; Jorgensen, W. L.; Lins, R. D.; Briggs, J. M.; McCammon, J. A. Developing a dynamic pharmacophore model for HIV-1 integrase J. Med. Chem. 2000, 43, 2100-2114 10.1021/jm990322h
18. Cocohoba, J.; Dong, B. J. Raltegravir: the first HIV integrase inhibitor Clin. Ther. 2008, 30, 1747-1765 10.1016/j.clinthera.2008.10.012
19. 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, 5843-5855 10.1021/jm800245z
20. Shimura, K.; Kodama, E. N. Elvitegravir: a new HIV integrase inhibitor Antiviral Chem. Chemother. 2009, 20, 79-85 10.3851/IMP1397
21. Vandekerckhove, L. GSK-1349572, a novel integrase inhibitor for the treatment of HIV infection Curr. Opin. Invest. Drugs 2010, 11, 203-212
22. 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, 254-258 10.1128/AAC.00842-09
23. Shafer, R. W. Rationale and uses of a public HIV drug-resistance database J. Infect. Dis. 2006, 194 (Suppl. 1) S51-S58 10.1086/505356
24. Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. N-3 hydroxylation of pyrimidine-2,4-diones yields dual inhibitors of HIV reverse transcriptase and integrase ACS Med. Chem. Lett. 2011, 2, 63-67 10.1021/ml1002162
25. Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. Q. 6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase Bioorg. Med. Chem. Lett. 2011, 21, 2400-2402 10.1016/j.bmcl.2011.02.069
26. Tang, J.; Maddali, K.; Metifiot, M.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. Q. 3-Hydroxypyrimidine-2,4-diones as an inhibitor scaffold of HIV integrase J. Med. Chem. 2011, 54, 2282-2292 10.1021/jm1014378
27. Tang, J.; Maddali, K.; Dreis, C. D.; Sham, Y. Y.; Vince, R.; Pommier, Y.; Wang, Z. Q. 6-Benzoyl-3-hydroxypyrimidine-2,4-diones as dual inhibitors of HIV reverse transcriptase and integrase Bioorg. Med. Chem. Lett. 2011, 21, 2400-2402 10.1016/j.bmcl.2011.02.069
28. Vernekar, S. K.; Liu, Z.; Nagy, E.; Miller, L.; Kirby, K. A.; Wilson, D. J.; Kankanala, J.; Sarafianos, S. G.; Parniak, M. A.; Wang, Z. Design, synthesis, biochemical, and antiviral evaluations of C6 benzyl and C6 biarylmethyl substituted 2-hydroxylisoquinoline-1,3-diones: dual inhibition against HIV reverse transcriptase-associated RNase H and polymerase with antiviral activities J. Med. Chem. 2015, 58, 651-664 10.1021/jm501132s
29. Mai, X.; Lu, X. S.; Xia, H. Y.; Cao, Y. S.; Liao, Y. J.; Lv, X. L. Synthesis, antitumor evaluation and crystal structure of hydroxyurea derivatives Chem. Pharm. Bull. 2010, 58, 94-97 10.1248/cpb.58.94
30. Stadlbauer, W.; Badawey, E. S.; Hojas, G.; Roschger, P.; Kappe, T. Malonates in cyclocondensation reactions Molecules 2001, 6, 338-352 10.3390/60400338
31. Arnott, E. A.; Chan, L. C.; Cox, B. G.; Meyrick, B.; Phillips, A. POCl3 chlorination of 4-quinazolones J. Org. Chem. 2011, 76, 1653-1661 10.1021/jo102262k
32. Kotera, M.; Ishii, K.; Tamura, O.; Sakamoto, M. 1,3-dipolar cycloadditions of photoinduced carbonyl ylides. Part 2. Photoreactions of alpha,beta-unsaturated gamma,delta-epoxy dinitriles and ethyl vinyl ether J. Chem. Soc., Perkin Trans. 1 1998, 313-318 10.1039/a704632d
33. Lee, I. Y.; Lee, J. Y.; Gong, Y. D. Microwave-assisted facile one-step carbamoylation of 6-aminouracils Synthesis 2005, 2713-2717 10.1055/s-2005-872099
34. Fletcher, S.; Gunning, P. T. Mild, efficient and rapid O-debenzylation of ortho-substituted phenols with trifluoroacetic acid Tetrahedron Lett. 2008, 49, 4817-4819 10.1016/j.tetlet.2008.06.022
35. Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays J. Immunol. Methods 1983, 65, 55-63 10.1016/0022-1759(83)90303-4
36. Sirivolu, V. R.; Vernekar, S. K. V.; Ilina, T.; Myshakina, N. S.; Parniak, M. A.; Wang, Z. Q. Clicking 3 ′-azidothymidine into novel potent inhibitors of human immunodeficiency virus J. Med. Chem. 2013, 56, 8765-8780 10.1021/jm401232v
37. Kimpton, J.; Emerman, M. Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated beta-galactosidase gene J. Virol. 1992, 66, 2232-2239
38. Metifiot, M.; Marchand, C.; Maddali, K.; Pommier, Y. Resistance to integrase inhibitors Viruses 2010, 2, 1347-1366 10.3390/v2071347
39. Metifiot, M.; Maddali, K.; Naumova, A.; Zhang, X.; Marchand, C.; Pommier, Y. Biochemical and pharmacological analyses of HIV-1 integrase flexible loop mutants resistant to raltegravir Biochemistry 2010, 49, 3715-3722 10.1021/bi100130f
40. da Silva, D.; Van Wesenbeeck, L.; Breilh, D.; Reigadas, S.; Anies, G.; Van Baelen, K.; Morlat, P.; Neau, D.; Dupon, M.; Wittkop, L.; Fleury, H.; Masquelier, B. HIV-1 resistance patterns to integrase inhibitors in antiretroviral-experienced patients with virological failure on raltegravir-containing regimens J. Antimicrob. Chemother. 2010, 65, 1262-1269 10.1093/jac/dkq099
41. Reuman, E. C.; Bachmann, M. H.; Varghese, V.; Fessel, W. J.; Shafer, R. W. Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector Antimicrob. Agents Chemother. 2010, 54, 934-936 10.1128/AAC.01345-09
42. Fantauzzi, A.; Mezzaroma, I. Dolutegravir: clinical efficacy and role in HIV therapy Ther. Adv. Chronic Dis. 2014, 5, 164-177 10.1177/2040622314530461
43. Nowotny, M. Retroviral integrase superfamily: the structural perspective EMBO Rep. 2009, 10, 144-151 10.1038/embor.2008.256
44. Esposito, D.; Craigie, R. HIV integrase structure and function Adv. Virus Res. 1999, 52, 319-333 10.1016/S0065-3527(08)60304-8
45. Goldgur, Y.; Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Craigie, R.; Davies, D. R. Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 9150-9154 10.1073/pnas.95.16.9150
46. Dyda, F.; Hickman, A. B.; Jenkins, T. M.; Engelman, A.; Craigie, R.; Davies, D. R. Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases Science 1994, 266, 1981-1986 10.1126/science.7801124
47. O'Brien, C. HIV integrase structure catalyzes drug search Science 1994, 266, 1946 10.1126/science.7801119
48. Hare, S.; Gupta, S. S.; Valkov, E.; Engelman, A.; Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer Nature 2010, 464, 232-236 10.1038/nature08784
49. Hare, S.; Vos, A. M.; Clayton, R. F.; Thuring, J. W.; Cummings, M. D.; Cherepanov, P. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20057-20062 10.1073/pnas.1010246107
50. Hare, S.; Smith, S. J.; Metifiot, M.; Jaxa-Chamiec, A.; Pommier, Y.; Hughes, S. H.; Cherepanov, P. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572) Mol. Pharmacol. 2011, 80, 565-572 10.1124/mol.111.073189
51. Krishnan, L.; Li, X.; Naraharisetty, H. L.; Hare, S.; Cherepanov, P.; Engelman, A. Structure-based modeling of the functional HIV-1 intasome and its inhibition Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 15910-15915 10.1073/pnas.1002346107
52. Wang, Z.; Bennett, E. M.; Wilson, D. J.; Salomon, C.; Vince, R. Rationally designed dual inhibitors of HIV reverse transcriptase and integrase J. Med. Chem. 2007, 50, 3416-3419 10.1021/jm070512p
53. Leh, H.; Brodin, P.; Bischerour, J.; Deprez, E.; Tauc, P.; Brochon, J. C.; LeCam, E.; Coulaud, D.; Auclair, C.; Mouscadet, J. F. Determinants of Mg2+dependent activities of recombinant human immunodeficiency virus type 1 integrase Biochemistry 2000, 39, 9285-9294 10.1021/bi000398b
54. Semenova, E. A.; Johnson, A. A.; Marchand, C.; Davis, D. A.; Yarchoan, R.; Pommier, Y. Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by α-hydroxytropolones Mol. Pharmacol. 2006, 69, 1454-1460 10.1124/mol.105.020321
55. Parniak, M. A.; Min, K. L.; Budihas, S. R.; Le Grice, S. F.; Beutler, J. A. A fluorescence-based high-throughput screening assay for inhibitors of human immunodeficiency virus-1 reverse transcriptase-associated ribonuclease H activity Anal. Biochem. 2003, 322, 33-39 10.1016/j.ab.2003.06.001
56. Abram, M. E.; Parniak, M. A. Virion instability of human immunodeficiency virus type 1 reverse transcriptase (RT) mutated in the protease cleavage site between RT p51 and the RT RNase H domain J. Virol. 2005, 79, 11952-11961 10.1128/JVI.79.18.11952-11961.2005
57. Sastry, G. M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments J. Comput.-Aided Mol. Des. 2013, 27, 221-234 10.1007/s10822-013-9644-8
58. Schrödinger Release 2014-3: Schrödinger Suite 2014-3 Protein Preparation Wizard; Epik, version 2.9; Impact, version 6.4; Prime, version 3.7; Schrödinger, LLC, New York, NY, 2014.
59. Jorgensen, W. L.; Maxwell, D. S.; TiradoRives, J. Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids J. Am. Chem. Soc. 1996, 118, 11225-11236 10.1021/ja9621760
60. Friesner, R. A.; Banks, J. L.; Murphy, R. B.; Halgren, T. A.; Klicic, J. J.; Mainz, D. T.; Repasky, M. P.; Knoll, E. H.; Shelley, M.; Perry, J. K.; Shaw, D. E.; Francis, P.; Shenkin, P. S. Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy J. Med. Chem. 2004, 47, 1739-1749 10.1021/jm0306430