Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV

Current Topics in Medicinal Chemistry

Volumn 8, Issue 13, 2008, Pages 1140-1151

  Price, David A ^a   Armour, Duncan ^b   de Groot, Marcel ^b   Leishman, Derek ^b   Napier, Carolyn ^b   Perros, Manos ^b   Stammen, Blanda L ^b   Wood, Anthony ^b  

^a PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United States)

^b PFIZER GLOBAL RESEARCH AND DEVELOPMENT   (United Kingdom)

Author keywords

Antagonist; Blockade; Hydrophobic interactions; Lipophilicity; Maraviroc; Treatment of HIV

Indexed keywords

AMITRIPTYLINE; AZETIDINE ACETAMIDE; BENZIMIDAZOLE DERIVATIVE; CHEMOKINE RECEPTOR CCR5 ANTAGONIST; CISAPRIDE; CLOFILIUM; DESIPRAMINE; DOFETILIDE; FLECAINIDE; FLUVOXAMINE; HALOPERIDOL; IMIPRAMINE; KETANSERIN; MACROPHAGE INFLAMMATORY PROTEIN 1BETA; MARAVIROC; OLANZAPINE; OXOGRANATANE; PIMOZIDE; POTASSIUM CHANNEL HERG; PROPAFENONE; QUETIAPINE; QUINIDINE; RISPERIDONE; TERFENADINE; TERODILINE; THIORIDAZINE; TRIAZOLE DERIVATIVE; UK 408030; UNCLASSIFIED DRUG;

ANTIVIRAL ACTIVITY; BINDING ASSAY; CHEMICAL MODIFICATION; CLINICAL TRIAL; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG EFFICACY; DRUG HALF LIFE; DRUG METABOLISM; DRUG PENETRATION; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG RESPONSE; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; HIGH THROUGHPUT SCREENING; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; HYDROPHOBICITY; LIPOPHILICITY; MONOTHERAPY; NONHUMAN; PHARMACOPHORE; PHYSICAL CHEMISTRY; PKA; REVIEW; STRUCTURE ACTIVITY RELATION;

ANTI-HIV AGENTS; CYCLOHEXANES; DRUG EVALUATION, PRECLINICAL; ETHER-A-GO-GO POTASSIUM CHANNELS; HUMANS; RECEPTORS, CCR5; TRIAZOLES;

EID: 52949106469     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802608785700007     Document Type: Review

References (34)

1. AIDS Epidemic Update, December 2005; UNAIDS/03.39E; World Health Organisation, 2005 (www.who,int/hiv/epi-update2005f_en.pdf).
2. Fauci, A. S. HIV and AIDS: 20 Years of Science. Nat. Med. 2003, 9, 839-843.
3. Carr, A. Toxicity of Antiretroviral Therapy and Implications for Drug Development. Nat. Rev. Drug Discov. 2003, 2, 624-634.
4. Duran, S.; Saves, M.; Spire, B.; Cailleton, V.; Sobel, A.; Carrieri, P.; Salmon, D.; Moatti, J. P.; Leport, C. Failure to Maintain Long Term Adherence to Highly Active Antiretroviral Therapy: the Role of Lipodistrophy. AIDS 2001, 15, 2441-2444.
5. Maddon, P. J.; Dalgleish, A. G.; McDougal, J. S.; Clapham, P. R.;, Weiss, R. A.; Axel, R. The T4 Gene Encodes the AIDS Virus Receptor and is Expressed in the Immune System and the Brain. Cell 1986, 47(3), 33-48.
6. Berger, E. A.; Murphy, P. M.; Farber, J. M. Chemokine receptors as HIV-1 Coreceptors. Roles in Viral Entry, Tropism and Disease. Annu. Rev. Immunol. 1999, 17, 657-700.
7. Liu, R.; Paxton, W. A.; Choe, S.; Ceradini, D.; Martin, S. R.; Horuk, R.; Macdonald, M. E.; Stuhlmann, H.; Koup, R. A.; Landau, N. R. Homozygous Defect in HIV-1 Coreceptor Accounts for the Resistance of Some Multiple-exposed Individuals to HIV-1 Infection. Cell 1996, 86, 367-377.
8. Michael. N. L.; Chang. G.; Louie, L. G.; Mascola, J. R.; Dondero, D.; Birx, D. L.; Sheppard, H. W. The Role of Viral Phenotype and CCR5 Gene Defects in HIV-1 Transmission and Disease Progression. Nat. Med. 1997, 3, 338-340.
9. Palani, A.; Tagat, J. R. Discovery and Development of Small-molecule Chemokine Coreceptor Anatagonists. J. Med. Chem. 2006, 49, 2851-2857.
10. Fermini, B.; Fossa, A. A. The Impact of Drug Induced QT Interval Prolongation on Drug Discovery and Development. Nat. Rev. Drug Discov. 2003, 2, 439-447.
11. Keiting, M. T.; Sanguinetti, M. C. Molecular and Cellular Mechanisms of Cardiac Arrhythmias. Cell 2001, 104, 569-580.
12. + Channel. A Model for Bad Behaviour. J. Med. Chem. 2003, 46, 2017-2022.
13. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal Chemistry of hERG Optimizations: Highlights and Hang-ups. J. Med. Chem. 2006, 49, 1-17.
14. Kim, D.; Wang, L.; Hare, J. J.; Lynch, U. L.; Budhu, R. J.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; Demartino, J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Hrin, R. C.; Carver, G.; Carella, A.; Henry, K.; Lineberger, J.; Schleif, W. A,; Emini, E. A. Potent 1,3,4-trisubstituted Pyrrolidine CCR5 Receptor Antagonists: Effects of Fused Heterocycles on Antiviral Activity and Pharmacokinetic Properties. Biorg. Med. Chem. Lett. 2005, 15, 2129-2134.
15. th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, February 24-28, 2002; Abstract 1, p 53.
16. Armour, D.; de Groot, M. J.; Edwards, M.; Perros, M.; Price, D. A.; Stammen, B. L.; Wood, A. The Discover of CCR5 Receptor Antagonists for the Treatment of HIV Infection: Hit-to-lead Studies. Chem. Med. Chem. 2006, 1, 706-709.
17. Armour, D.; de Groot, M. J.; Perros; M.; Price, D. A.; Stammen, B. L.; Wood, A.; Burt, C. The Discovery of Tropane-derived CCR5 Receptor Antagonists. Chem. Biol. Drug. Des. 2006, 67, 305-308.
18. 3H]-Dofetilide Binding to hERG Transfected Membranes: a Potential High Throughput Preclinical Screen. Eur. J. Pharmacol. 2001, 430, 147-148.
19. Greengrass, P. M.; Stewart, M.; Wood, C. M.; Patent Application WO 03021271.
20. + Channels. J. Pharm. Sci. 95, 311-319.
21. Liu, H.; Ji, M.; Luo, X.; Shen, J.; Huang, X.; Hua, W.; Jiang, H.; Chen, K. New p-Methylsulfonamido Phenylethylamine Analogues as Class III Antiarrhythmic Agents: Design, Synthesis, Biological Assay, and 3D-QSAR Analysis. J. Med. Chem. 2002, 45, 2953-2969.
22. Domene, C.; Haider, S.; Sansom, M. S. P. Ion channel structures: A review of recent progress. Curr. Opin. Drug Disc. Dev. 2003, 6, 611-619.
23. Mitcheson, J., S.; Chen, J.; Lin, M,; Culberson, C.; Sanguinetti, M. C. A Structural Basis for Drug-induced Long QT Syndrome. Proc. Nat. Acad. Sci. USA 2000, 97, 12329-12333.
24. Cavalli, A.; Poluzzi, E.; De Ponti, F.; Recanatini, M. Toward a Pharmacophore for Drugs Inducing the Long QT Syndrome: Insights from a CoMFA study of HERG K+ Channel Blockers. J. Med. Chem. 2002, 45, 3844-3853.
25. Perry, M.; de Groot M. J.; Helliwell, R.; Leishman, D.; Tristani-Firouzi, M.; Sanguinetti, M. C., Mitcheson, J. Structural Determinants of HERG Channel Block by Clofilium and Ibutilide. Mol. Pharmacol. 2004, 66, 240-249.
26. Artursson, P.; Palm, K.; Luthman, K. Caco-2 Monolayers in Experimental and Theoretical Predictions of Drug Transport. Adv. Drug Deliv, Rev. 1996, 12, 67-84.
27. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Adv. Drug Deliv. Rev. 1997, 23, 3-25.
28. Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P. S. The Influence of Peptide Structure on Transport Across Caco-2 Cells. Pharm. Res. 1991, 8, 1453-1460.
29. Palm, K.; Stenberg, P.; Luthman, K.; Attursson, P. Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans. Pharm. Res. 1997, 14, 568-571.
30. Holladay, M. W.; Salituro, F. G.; Rich, D. H. Synthetic and Enzyme Inhibition Studies of Pepstatin Analogs Containing Hydroxyethylene and Ketomethylene Dipeptide Isosteres. J. Med Chem. 1987, 30, 374-383.
31. Price, D. A.; Armour, D.; de Groot, M.J.; Leishman, D.; Napier, C.; Perros, M.; Stammen, B. L.; Wood, A. Overcoming hERG Affinity in the Discovery of the CCR5 Antagonist. Maraviroc. Biorg. Med. Chem. Lett. 2006, 16, 4633-4637.
32. Price, D. A.; Gayton, S.; Selby, M. D.; Ahman, J.; Haycock-Lewandowski, S. A Practical Synthesis of Piperidine-tropane-substituted 1,2,4-Triazoles. Synlett 2005, 7, 1133-1134.
33. Price, D. A.; Gayton, S.; Selby, M. D.; Ahman, J.; Haycock-Lewandowski, S.; Stammen, B. L.; Warren, A. Initial Synthesis of UK-427,857 (Maraviroc). Tetrahedron Lett. 2005, 46, 5005-5007.
34. Dorr, P.; Westhy, M.; Dobbs, S.; Griffin, P.; Irvine, B.; Macartney, M.; Mori, J.; Rickett, G.; Smoth-Burchnell, C.; Napier, C.; Webster, R.; Armour, D.; Price, D.; Stammen, B.; Woor A; Perros, M. Maraviroc (UK427,857), a Potent Orally Bioavailable, and Selective Small-Molecule Inhibitor of Chemokine Receptor CCR5 with Broad-Spectrum Anti-Human Immunodeficiency Virus Type 1 Activity. Antimicrob. Agents Chemother. 2005, 49, 4721-4732.