It:Maraviroc
Maraviroc is a specific CCR5 antagonist with potent Anti-human immunodeficiency virus type 1 (HIV-1) activity and effective pharmacological properties against HIV. The human receptor, CCR5, is an attractive target for discovery of viral entry inhibitors and Maraviroc is the product of a high-throughput screen of the Pfizer compound file, and is currently in Phase 3 clinical trial.
Maraviroc |
Treatment against HIV
Recently, the treatment of HIV infection has been significantly improved by Highly Active Anti- Retroviral Therapy (HAART) and has brought better prognosis for HIV sufferers. However, the highly demanding anti-retroviral drug dosing regimen and an extensive range of adverse effects associated with HAART means new viral therapies are needed to establish a more tolerable drug regimen.
Synthesis of Maraviroc
There are overall 6 steps involved in the synthesis of Maraviroc and the two main reagents are commercially available -amino acid (1) and tropinone(4).
Reaction of -amino acid (1) with a protecting group Z for the primary amine, followed by saponification in the first step produces 72% of carboxylic acid (2). The acid (2) is then converted to an aldehyde (3) via reduction with BH3 followed by oxidation using SO3.
Tropinone (4) undergoes oxime formation and then reduction by sodium in pentanol to yield tropane (5) in which -NH2 is equatorially substituted. This amine is reacted with isobutyryl chloride and phosphorous pentachloride in situ with acetic hydrazide to produce 1,3,4-triazole moiety. This is then cyclised to triazole by thermally heating it in toluene and the benzyl protecting group removed by hydrogenation to form amine (6).
Reductive amination of aldehyde (3) and amine (6) in NaBH(OAc)3 produces tropane (7). The protecting group Z for the primary amine is then removed via hydrogenation. Reaction of tropane (7) with 4,4-difluorocyclohexyl carboxylic acid (8) finally completes the synthesis of Maraviroc.
References
1.Dorr, Patrick; 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. 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 (2005), 49(11), 4721-4732. CODEN: AMACCQ ISSN:0066-4804. CAN 143:432085 AN 2005:1201940 CAPLUS
2. Pfizer, Sandwich Drug Discoveries, printed October 2006