MARAVIROC

MARAVIROC

UK-427857; Selzentry; Celsentri

376348-65-1  CAS NO

Maraviroc M.Wt: 513.67
Maraviroc Formula: C29H41F2N5O

Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor. It also appeared to reduce graft-versus-host disease in patients treated withallogeneic bone marrow transplantation for leukemia, in a phase 1/2 study.[3][4]

Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor, which is found on the surface of certain human cells. The chemokine receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter humanmacrophages and T-cells.[5] Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.[6]

Development and approval

Maraviroc, originally designated UK-427857, was developed by the drug company Pfizer in its UK labs located in Sandwich. On April 24, 2007 the U.S. Food and Drug Administration advisory panel reviewing maraviroc’s New Drug Application unanimously recommended approval for the new drug,[7] and the drug received full FDA approval on August 6, 2007 for use in treatment experienced patients.[8]

On September 24, 2007, Pfizer announced that the European Commission approved maraviroc. Industry experts forecast annual maraviroc sales of $500 million by 2011.[9]

SELZENTRY (maraviroc) is a selective, slowly reversible, small moleculeantagonist of the interaction between human CCR5 and HIV-1 gp120. Blocking this interaction prevents CCR5-tropic HIV-1 entry into cells.

SELZENTRY is available as film-coated tablets for oral administration containing either 150 or 300 mg of maraviroc and the following inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, microcrystalline cellulose, and sodium starch glycolate. The film coat (Opadry® II Blue [85G20583]) contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol (macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide.

Maraviroc is chemically described as 4,4-difluoro-#-((15′)-3-[exo-3-(3-isopropyl-5- methyl-4#-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1- phenylpropyl} cycl ohexanecarboxamide.

The molecular formula is C29H41F2N5O and the structural formula is:

Maraviroc is a white to pale-colored powder with a molecular weight of 513.67. It is highly soluble across the physiological pH range (pH 1.0 to 7.5).

Two randomized, placebo-controlled clinical trials, known as MOTIVATE 1 & 2, compared 209 patients receiving optimized therapy plus a placebo to 426 patients receiving optimized therapy plus 150 mg maraviroc once daily and 414 patients receiving optimized therapy plus 150 mg maraviroc twice daily. At 48 weeks, 55% of participants receiving maraviroc once daily and 60% of participants receiving the drug twice daily achieved a viral load of less than 400 copies/mL compared with 26% of those taking placebo; about 44% of the once-daily and 45% of the twice-daily maraviroc group had a viral load of less than 50 copies/mL compared with about 23% of those who received placebo. In addition, those who received the entry inhibitor had a mean increase in CD4 cells of 110 cells/µL in the once-daily group, 106 cells/µL in the twice-daily group, and 56 cells/µL in the placebo group.[10][11][12]

The MOTIVATE trials showed no clinically relevant differences in safety between the maraviroc and placebo groups. However, researchers question the long-term safety of blocking CCR5, a receptor whose function in the healthy individual is not fully understood.[10]

1.  Abel S, Russell D, Whitlock LA, Ridgway CE, Nedderman AN, Walker DK (April 2008). “Assessment of the absorption, metabolism and absolute bioavailability of maraviroc in healthy male subjects”. British Journal of Clinical Pharmacology 65 (Suppl 1): 60–7. doi:10.1111/j.1365-2125.2008.03137.x. PMC 2311408. PMID 18333867.
2.  Abel S, Back DJ, Vourvahis M (2009). “Maraviroc: pharmacokinetics and drug interactions”. Antiviral Therapy 14 (5): 607–18. PMID 19704163.
3.  http://www.uphs.upenn.edu/news/News_Releases/2012/07/hiv/
4.  Blocade of lymphocyte chemotaxis in visceral graft-versus-host disease, Ran Reshef et al., New England Journal of Medicine, 367:135 (July 12, 2012)
5.  Levy JA (January 2009). “HIV pathogenesis: 25 years of progress and persistent challenges”. AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f. PMID 19098484.
6.  Biswas P, Tambussi G, Lazzarin A (May 2007). “Access denied? The status of co-receptor inhibition to counter HIV entry”. Expert Opinion on Pharmacotherapy 8 (7): 923–33.doi:10.1517/14656566.8.7.923. PMID 17472538.
7.  Gay News From 365Gay.com
8.  Krauskopf, Lewis (August 6, 2007). “Pfizer wins U.S. approval for new HIV drug”. Reuters. Retrieved 2007-08-06.
9.  Reuters, Europe gives final approval to Pfizer HIV drug
10. ^ Jump up to:a b Stephenson J (April 2007). “Researchers buoyed by novel HIV drugs: will expand drug arsenal against resistant virus”. JAMA 297 (14): 1535–6. doi:10.1001/jama.297.14.1535.PMID 17426263.
11.  Emmelkamp JM, Rockstroh JK (October 2007). “CCR5 antagonists: comparison of efficacy, side effects, pharmacokinetics and interactions–review of the literature”. European Journal of Medical Research 12 (9): 409–17. PMID 17933722.
12.  ”Maraviroc reduces viral load in naive patients at 48 weeks”. AIDS Patient Care and STDs 21 (9): 703–4. September 2007. PMID 17941136.

• BBC News story: Drug ‘stops HIV’s entry to cells’
• Maraviroc data at aidsmap
• Maraviroc early access program
• New HIV Drug Recommended for Approval
• maraviroc at the US National Library of Medicine Medical Subject Headings (MeSH)

…………………

Maraviroc and its pharmaceutically acceptable salt or solvate thereof were disclosed in U.S. Patent No. 6,667,314 (herein after refer to ’314 patent). Maraviroc is chemically, N- {(lS)-3-[3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8-azabicyclo- [3.2.1]oct-8-yl]-l- phenylpropyl}-4,4-difluorocyclohexanecarboxamide and has the structural formula:

Maraviroc as modulators of the chemokine receptor CCR5 and thus useful in the treatment of retroviral diseases caused by viruses that utilize CCR5 to enter cells. In particular maraviroc has been disclosed as being a useful therapeutic in the treatment of HIV, a retroviral infection genetically related to HIV, AIDS, or an inflammatory disease.

Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other

Maraviroc or its salts can exist in different polymorphic forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.

According to the ’314 patent, maraviroc can be prepared by reacting a solution of (l S)-3-[3-(3-isopropyl-5-methyl-4H-l,2,4-triazol-4-yl)-exo-8-azabicyclo[3.2.1]oct-8-yl]-l- phenyl- 1 -propanamine in methylene chloride and saturated sodium carbonate with a solution of 4,4-difluorocyclohexanecarbonyl chloride in toluene, and isolating to obtain maraviroc.

Crystalline polymorph form A and form B of maraviroc were disclosed in U.S. patent no. 7,576,097.

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin

Innovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK

 Corresponding author email

Editor-in-Chief: J. Clayden

Beilstein J. Org. Chem. 2011, 7, 442–495.

A novel and very promising HIV treatment is Pfizer’s maraviroc (286, Celsentri). HIV uses a member of the G-protein coupled receptor family called CCR-5 as an anchor to attach itself to white blood cells such as T-cells and macrophages followed by viral fusion and entry into white blood cells. Maraviroc blocks this pathway by acting as an antagonist for the CCR-5 receptor hence disrupting HIV life cycle. The structural features of this molecule are a geminal difluorocyclohexyl carboxamide which is linked to a β-aminoacid, and a tropinone-type unit bound to a 1,2,4-triazole ring. Relatively simple and straightforward chemical transformations are used to assemble the main fragments of maraviroc such as amide bond formation and reductive amination (Scheme 57) [86]. The triazole ring incorporation is achieved at an early stage by N-acylation of the tropinone fragment 287 with 2-methylpropanoyl chloride (288). The resulting amide 289 is then converted to the corresponding imidoyl chloride 290 using phosphorous pentachloride in dichloromethane (which proved to be superior to phosphoryl chloride) followed by condensation with acetic hydrazide (291). It was found that the dryness of the acetic hydrazide was crucial in order to minimise the hydrolysis of the starting amide 289.

Scheme 57: Synthesis of maraviroc.

Haycock-Lewandowski, S. J.; Wilder, A.; Åhman, J. Org. Process Res. Dev. 2008, 12, 1094–1103.doi:10.1021/op8000614

 …………………………………

nmr

UK

 

TET LETT 46, 2005, PG5005