Initial synthesis of UK-427,857 (Maraviroc)

Price, David A.; Gayton, Simon; Selby, Matthew D.; Åhman, Jens; Haycock-Lewandowski, Sarah J.; Stammen, Blanda; Warren, Andrew N.

doi:10.1016/j.tetlet.2005.05.082

Cited by 51 publications

(45 citation statements)

References 9 publications

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“…The cloudy combined filtrates were filtered through a Celite pad, the chloroform was evaporated in vacuo, and the colorless oil was dried under high vacuum to afford a white foam, which was subsequently recrystallized from toluene/hexanes (2:1) to afford a white solid (0.65 g; 73%; mp, 189 to 191°C), which matched the IPM reference standard. A 1 H nuclear magnetic resonance spectrum of this material closely matched published data (20) and data for the IPM reference standard, confirming purity.…”

Section: Materials Tenofovir Disoproxil Fumarate (Tdf) and Emtricitasupporting

confidence: 79%

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Moss

Srinivasan

Smith

et al. 2014

Antimicrob Agents Chemother

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Preexposure prophylaxis (PrEP) using FDA-approved antiretroviral (ARV) drugs is emerging as a promising strategy for the prevention of sexual HIV infection. There is growing consensus that a combination of ARV agents, analogous to highly active antiretroviral therapy (HAART), likely is essential for optimally effective PrEP (1, 2). Oral administration of tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) (Truvada; Gilead Sciences, Inc.) is the first regimen approved by the FDA to reduce the risk of HIV infection in uninfected individuals (http://www.fda.gov/NewsEvents/Newsroom /PressAnnouncements/ucm312210.htm). Three recent clinical trials demonstrated that oral ARV regimens using the combination of TDF and FTC can be effective in susceptible men, women, and partners of HIV-infected individuals (3-5). However, the relative risk reduction in these trials varied widely (from 44 to 75%), and a study in which women used a daily oral TDF-FTC regimen was stopped early due to futility. A critical factor driving success in these trials appears to involve sustaining high levels of adherence to frequent dosing (6).It is well established across different delivery methods that adherence to therapy is inversely related to the dosing period (7-10). Controlled topical delivery of ARV drugs using intravaginal rings (IVRs) is thought to improve adherence (11) and to provide sustained mucosal levels independent of coitus and daily dosing (12). The delivery of two or more ARV drugs from conventional IVR designs involves significant technological and manufacturing hurdles. To meet these challenges, we have developed a novel IVR technology, the pod-IVR (13), that enables rapid development of devices capable of delivering multiple agents over a wide range of target delivery rates and aqueous solubilities (14-16). We recently published the design and 28-day pharmacokinetic (PK) evaluation in sheep of a five-drug pod-IVR as a proof-of-concept, advanced multipurpose prevention technology (MPT), combining three ARV drugs from different mechanistic classes (tenofovir [TFV], nevirapine, and saquinavir) with a proven estrogen-progestogen contraceptive for prevention of HIV infection and unintended pregnancy (17).Here we present the first report of an IVR delivering TDF and FTC, as well as the first report of a triple-combination IVR delivering TDF, FTC, and maraviroc (MVC) (an entry inhibitor/antagonist of chemokine receptor 5 [CCR5]). Preliminary local safety and pharmacokinetic (PK) findings for these devices were determined in pig-tailed macaques, which are considered by many to represent the most relevant animal model for HIV vaginal PrEP studies (15,18,19). Steady-state drug levels for all three ARV agents in vaginal fluids were sustained over the 28-day study period, with corresponding vaginal tissue concentrations suggesting putative efficacy in preventing HIV infection.

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Section: Materials Tenofovir Disoproxil Fumarate (Tdf) and Emtricitasupporting

confidence: 79%

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Moss

Srinivasan

Smith

et al. 2014

Antimicrob Agents Chemother

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“…The pioneering synthesis of maraviroc ( 2 ) by Pfizer 9-11 had established the feasibility of forming the same C–N bond by reductive amination after attempts at displacing a primary mesylate by the secondary amine of the tropane fragment had failed to provide greater than 20 percent yield of 2 under a variety of conditions. While the difficulties that the Pfizer group had encountered in alkylations of the tropane building block with primary methanesulfonate esters were a concern, we reasoned that the conformationally-constrained nature and the electron-withdrawing acyl group of cyclic sulfamate 9 would heighten the intrinsic electrophilic reactivity of the terminal carbon that would be attacked by the secondary amine of compound 6 .…”

Section: Resultsmentioning

confidence: 99%

“…The pioneering and highly convergent medicinal chemistry 9 and process chemistry 10,11 syntheses of maraviroc ( 2 ) by Pfizer (Scheme 1) utilized an intermolecular Mannich/enantiomer resolution process to produce β-amino ester 4 , a key intermediate that was subsequently employed in coupling reactions with 4,4-difluorocyclohexane-1-carboxylic acid 5 and tropane triazole 6 12 to complete the synthesis. The subsequent syntheses of maraviroc by the laboratories of Schaus 13 and Cordóva 14 retained the logic of Pfizer's convergent synthesis design and featured chiral catalyst-controlled, asymmetric allylation and aza-Michael reactions, respectively, to establish the absolute configuration of the nitrogen-bearing stereocenter of maraviroc ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

An expedient synthesis of maraviroc (UK-427,857) via C–H functionalization

Bedell

Hone

Bois

et al. 2015

Tetrahedron Letters

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“…135 The initial synthesis of maraviroc that produced material for preclinical studies has been published. 136,137 One of the reactions is catalyzed by TEMPO, where the alcohol is oxidized to give the required aldehyde, as shown in Scheme 37. 138 Darunavir is an antiretroviral drug in the HIV-1 protease inhibitor class for the treatment of multidrug-resistant HIV.…”

Section: Genotoxic Compounds Used As Reactantsmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

et al. 2015

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alkylation of the second nitrogen of the piperazine ring with the genotoxic reagent 4-chloro-1-bromobutane (Scheme 10). 64 APIs streams may contain genotoxic alkyl halides impurities when a reaction takes place in alcoholic solvent at reflux temperature in the presence of hydrogen halides or alkali halides and strong acids. These reaction conditions may be applied in cyclization, decarboxylation, sulfonyl cleavage, Narylation and API salt formation. Note that this list is not exhaustive. For instance, capecitabine is a chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. 65 During its synthesis, D-ribose is heated under reflux in methanol in the presence of concentrated HCI and acetone Scheme 2. O-Alkylation of Isovanillin during the Synthesis of Aliskiren Using Genotoxic 1,3-Dibromopropane Scheme 3. Use of Methyl Iodide in the Preparation of Cerivastatin Scheme 4. S-Alkylation with Methyl Iodide during the Last Synthetic Step of Lamifiban Scheme 5. S-Alkylation with Methyl Iodide during the Synthesis of Eldacimibe Scheme 6. N-Methylation with Genotoxic Methyl Iodide during the Preparation of Efegatran Scheme 7. Quaternization by Means of Methyl Iodide during Milameline Synthesis Scheme 8. Direct Use of Genotoxic 2-Iodopropane in the Synthesis of Latanoprost Scheme 9. Use of Genotoxic 2-Bromopropane and Nitrogen Mustard during the Synthesis of Mazapertine

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Initial synthesis of UK-427,857 (Maraviroc)

Cited by 51 publications

References 9 publications

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

Pharmacokinetics and Preliminary Safety Study of Pod-Intravaginal Rings Delivering Antiretroviral Combinations for HIV Prophylaxis in a Macaque Model

An expedient synthesis of maraviroc (UK-427,857) via C–H functionalization

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

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