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PMID: 16251317 Published · ppublish English Journal Article

Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity.

Antimicrobial agents and chemotherapy ·Vol. 49 ·No. 11 ·2005-11-00 ·Pages 4721-32

Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M

Abstract

Maraviroc (UK-427,857) is a selective CCR5 antagonist with potent anti-human immunodeficiency virus type 1 (HIV-1) activity and favorable pharmacological properties. Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file. Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM). Maraviroc was active against 200 clinically derived HIV-1 envelope-recombinant pseudoviruses, 100 of which were derived from viruses resistant to existing drug classes. There was little difference in the sensitivity of the 200 viruses to maraviroc, as illustrated by the biological cutoff in this assay (= geometric mean plus two standard deviations [SD] of 1.7-fold). The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry. Maraviroc did not affect CCR5 cell surface levels or associated intracellular signaling, confirming it as a functional antagonist of CCR5. Maraviroc has no detectable in vitro cytotoxicity and is highly selective for CCR5, as confirmed against a wide range of receptors and enzymes, including the hERG ion channel (50% inhibitory concentration, >10 microM), indicating potential for an excellent clinical safety profile. Studies in preclinical in vitro and in vivo models predicted maraviroc to have human pharmacokinetics consistent with once- or twice-daily dosing following oral administration. Clinical trials are ongoing to further investigate the potential of using maraviroc for the treatment of HIV-1 infection and AIDS.

MeSH Terms
Acquired Immunodeficiency Syndrome/drug therapy Animals Anti-HIV Agents/pharmacology Biological Availability CCR5 Receptor Antagonists Cyclohexanes/pharmacokinetics,pharmacology Dogs Drug Resistance, Viral Drug Therapy, Combination HIV-1/drug effects HeLa Cells Humans Male Maraviroc Membrane Fusion/drug effects Rats Rats, Sprague-Dawley Receptors, CCR5/metabolism Triazoles/pharmacokinetics,pharmacology
Chemicals
Anti-HIV Agents CCR5 Receptor Antagonists Cyclohexanes Receptors, CCR5 Triazoles Maraviroc
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Dorr Patrick
Discovery Biology, Pfizer Global Research and Development-Sandwich Laboratories, Kent CT13 9NJ, United Kingdom. patrick.dorr@pfizer.com
Westby Mike
Dobbs Susan
Griffin Paul
Irvine Becky
Macartney Malcolm
Mori Julie
Rickett Graham
Smith-Burchnell Caroline
Napier Carolyn
Webster Rob
Armour Duncan
Price David
Stammen Blanda
Wood Anthony
Perros Manos
References (53)
53 references, click to expand
  1. A three-dimensional model to analyze drug-drug interactions.
    Antiviral Res. 1990 Oct-Nov;14(4-5):181-205 PMID: 2088205
  2. Subtype-specific stimulation of [35S]GTPgammaS binding by recombinant alpha2-adrenoceptors.
    Eur J Pharmacol. 1998 Aug 21;355(2-3):275-9 PMID: 9760042
  3. The effect of a synthetic 7-thiaprostaglandin E1 derivative, TEI-6122, on monocyte chemoattractant protein-1 induced chemotaxis in THP-1 cells.
    Br J Pharmacol. 1995 Oct;116(4):2298-302 PMID: 8564263
  4. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.
    Nature. 1996 Jun 20;381(6584):667-73 PMID: 8649512
  5. Cloning and functional expression of CC CKR5, a human monocyte CC chemokine receptor selective for MIP-1(alpha), MIP-1(beta), and RANTES.
    J Leukoc Biol. 1996 Jul;60(1):147-52 PMID: 8699119
  6. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection.
    Cell. 1996 Aug 9;86(3):367-77 PMID: 8756719
  7. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.
    Nature. 1996 Aug 22;382(6593):722-5 PMID: 8751444
  8. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study.
    Science. 1996 Sep 27;273(5283):1856-62 PMID: 8791590
  9. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity.
    J Exp Med. 1998 Apr 20;187(8):1215-24 PMID: 9547333
  10. MHC class II tetramers identify peptide-specific human CD4(+) T cells proliferating in response to influenza A antigen.
    J Clin Invest. 1999 Dec;104(12):R63-7 PMID: 10606632
  11. The emerging role of fusion inhibitors in HIV infection.
    Drugs R D. 1999 Nov;2(5):321-31 PMID: 10728472
  12. Causal pathways for CCR5 genotype and HIV progression.
    J Acquir Immune Defic Syndr. 2000 Feb 1;23(2):160-71 PMID: 10737431
  13. Use of inhibitors to evaluate coreceptor usage by simian and simian/human immunodeficiency viruses and human immunodeficiency virus type 2 in primary cells.
    J Virol. 2000 Aug;74(15):6893-910 PMID: 10888629
  14. The effects of the 32-bp CCR-5 deletion on HIV transmission and HIV disease progression in individuals with haemophilia.
    Br J Haematol. 2000 Oct;111(1):136-42 PMID: 11091193
  15. The effect of genetic variation in chemokines and their receptors on HIV transmission and progression to AIDS.
    Immunol Rev. 2000 Oct;177:99-111 PMID: 11138790
  16. Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: a new strategy in the treatment of chronic inflammatory diseases and HIV.
    J Immunol. 2001 Feb 15;166(4):2420-6 PMID: 11160301
  17. Sensitivity of human immunodeficiency virus type 1 to fusion inhibitors targeted to the gp41 first heptad repeat involves distinct regions of gp41 and is consistently modulated by gp120 interactions with the coreceptor.
    J Virol. 2001 Sep;75(18):8605-14 PMID: 11507206
  18. Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5.
    J Biol Chem. 2001 Sep 14;276(37):35194-200 PMID: 11454872
  19. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo.
    Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12718-23 PMID: 11606733
  20. Acute HIV infection: impact on the spread of HIV and transmission of drug resistance.
    AIDS. 2001 Nov 23;15(17):2287-92 PMID: 11698702
  21. HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use.
    Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):395-400 PMID: 11782552
  22. Pharmacological characterization of the chemokine receptor, CCR5.
    Br J Pharmacol. 2002 Feb;135(4):1033-43 PMID: 11861332
  23. Adherence to HAART among patients with HIV: breakthroughs and barriers.
    AIDS Care. 2002 Jun;14(3):309-18 PMID: 12042076
  24. Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics.
    J Pharmacol Exp Ther. 2002 Jul;302(1):320-7 PMID: 12065733
  25. Antiretroviral-drug resistance among patients recently infected with HIV.
    N Engl J Med. 2002 Aug 8;347(6):385-94 PMID: 12167680
  26. Susceptibility of diverse primary HIV isolates with varying co-receptor specificity's to CXCR4 antagonistic compounds.
    J Med Virol. 2002 Oct;68(2):147-55 PMID: 12210401
  27. Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents.
    J Enzyme Inhib Med Chem. 2002 Apr;17(2):69-76 PMID: 12420752
  28. Enfuvirtide.
    Expert Opin Investig Drugs. 2002 Dec;11(12):1837-43 PMID: 12457443
  29. Highly potent RANTES analogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4-using variants.
    J Virol. 1999 May;73(5):3544-50 PMID: 10196243
  30. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.
    Annu Rev Immunol. 1999;17:657-700 PMID: 10358771
  31. Alpha2-adrenoceptor agonists stimulate high-affinity GTPase activity in a receptor subtype-selective manner.
    Eur J Pharmacol. 1999 Jun 11;374(1):137-46 PMID: 10422650
  32. Transmission of antiretroviral-drug-resistant HIV-1 variants.
    Lancet. 1999 Aug 28;354(9180):729-33 PMID: 10475184
  33. CCR5 antagonists for the treatment of HIV.
    Curr Opin Investig Drugs. 2004 Aug;5(8):851-61 PMID: 15600241
  34. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.
    Mol Pharmacol. 2005 Apr;67(4):1268-82 PMID: 15644495
  35. Pharmacokinetics and short-term safety of 873140, a novel CCR5 antagonist, in healthy adult subjects.
    Antimicrob Agents Chemother. 2005 Jul;49(7):2802-6 PMID: 15980352
  36. CCR5 chemokine receptors: gatekeepers of HIV-1 infection.
    Curr Drug Targets Infect Disord. 2002 Sep;2(3):265-78 PMID: 12462129
  37. Structure modeling of the chemokine receptor CCR5: implications for ligand binding and selectivity.
    Biophys J. 2002 Dec;83(6):3012-31 PMID: 12496074
  38. Travel and the spread of HIV-1 genetic variants.
    Lancet Infect Dis. 2003 Jan;3(1):22-7 PMID: 12505029
  39. Rapid evolution of the neutralizing antibody response to HIV type 1 infection.
    Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4144-9 PMID: 12644702
  40. Inhibitors of the entry of HIV into host cells.
    Curr Opin Drug Discov Devel. 2003 Jul;6(4):451-61 PMID: 12951808
  41. Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions.
    J Virol. 2003 Oct;77(19):10528-36 PMID: 12970437
  42. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11013-8 PMID: 12930892
  43. Natural variation of drug susceptibility in wild-type human immunodeficiency virus type 1.
    Antimicrob Agents Chemother. 2004 Feb;48(2):437-43 PMID: 14742192
  44. Is resistance futile?
    Curr Drug Targets Infect Disord. 2003 Dec;3(4):295-309 PMID: 14754431
  45. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist.
    J Med Chem. 2004 May 6;47(10):2405-8 PMID: 15115380
  46. Small-molecule antagonists of CCR5 and CXCR4: a promising new class of anti-HIV-1 drugs.
    Curr Pharm Des. 2004;10(17):2041-62 PMID: 15279544
  47. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.
    J Virol. 2004 Aug;78(16):8654-62 PMID: 15280474
  48. Development and automation of a 384-well cell fusion assay to identify inhibitors of CCR5/CD4-mediated HIV virus entry.
    J Biomol Screen. 2004 Sep;9(6):516-24 PMID: 15452338
  49. Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor.
    J Immunol. 1998 Apr 15;160(8):4018-25 PMID: 9558111
  50. Human immunodeficiency virus type 1 protease genotypes and in vitro protease inhibitor susceptibilities of isolates from individuals who were switched to other protease inhibitors after long-term saquinavir treatment.
    J Virol. 1998 Jun;72(6):5303-6 PMID: 9573309
  51. Interferon-inducible T cell alpha chemoattractant (I-TAC): a novel non-ELR CXC chemokine with potent activity on activated T cells through selective high affinity binding to CXCR3.
    J Exp Med. 1998 Jun 15;187(12):2009-21 PMID: 9625760
  52. Identification of C-C chemokine receptor 1 (CCR1) as the monocyte hemofiltrate C-C chemokine (HCC)-1 receptor.
    J Exp Med. 1998 Aug 3;188(3):603-8 PMID: 9687537
  53. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells.
    Science. 1995 Dec 15;270(5243):1811-5 PMID: 8525373
Article Info
Journal
Antimicrobial agents and chemotherapy
Abbr.
Antimicrob Agents Chemother
ISSN
0066-4804
DOI
10.1128/AAC.49.11.4721-4732.2005
Email
patrick.dorr@pfizer.com
Published
2005-11-00
Pages
4721-32
Language
English
Region
United States
NLM ID
0315061
PMCID
PMC1280117
Subset
IM
External Links
PubMed source DOI: 10.1128/AAC.49.11.4721-4732.2005 PMC Full Text View journal details
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