Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV

Abstract

Our structure-based design strategies which specifically target the HIV-1 protease backbone, resulted in a number of exceedingly potent nonpeptidyl inhibitors. One of these inhibitors, darunavir (TMC114), contains a privileged, structure-based designed high-affinity P2 ligand, 3(R),3a(S),6a (R)-bis-tetrahydrofuranylurethane (bis-THF). Darunavir has recently been approved for the treatment of HIV/AIDS patients harboring multidrug-resistant HIV-1 variants that do not respond to previously existing HAART regimens. Keywords protease inhibitors; darunavir; design and synthesisThe AIDS (acquired immunodeficiency syndrome) epidemic has become one of the most pressing medical concerns of our time. 1 The World Health Organization (WHO), as of 2006, estimated that over 40 million people are infected with HIV (human immunodeficiency virus), the causative agent of AIDS. 2 During replication in the HIV life-cycle, gag and gag-pol gene products are produced as precursor polyproteins which are subsequently processed by a virally encoded protease to provide structural proteins (p17, p24, p9 and p7) and essential viral enzymes, including protease (PR), reverse transcriptase (RT) and integrase (IN). 3 All three retroviral enzymes have been identified as potential drug targets. Specifically, the critical function of HIV protease has made it an important target for the treatment of HIV/AIDS. The approval of the first protease inhibitor (PI), saquinavir and its introduction into highly active antiretroviral therapy (HAART), with reverse transcriptase inhibitors, led to significantly enhanced HIV management and improved the quality of life of HIV/AIDS patients. 4Since the advent of the first PI, saquinavir, a number of PIs have been introduced in the regimens of highly active antiretroviral therapy or HAART. Thus improved HAART regimens have shown reduced viral load, increased CD4+ T-cell counts 5 and drastically lowered AIDSrelated deaths in the US and industrialized nations. 6 While HAART proved to be a large step forward, there are still serious drawbacks with the first generation anti-protease therapeutics. * Corresponding author. Tel.: 765-494-5323; fax: 765-496-1612; e-mail: akghosh@purdue.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. These include: (1) severe side effects and drug toxicities, (2) higher therapeutic doses due to "peptide-like" character, (3) costly synthesis which leads to high treatment cost, and perhaps the most alarming, (4) the rapid emergence of drug resistance. Indeed, the emergence of multidrug-resistant HIV strains has greatly compromised current...

New Validated Rp-HPLC Method for the Estimation of Darunavir in Bulk and Its Dosage Form

“…Proposed method is validated as per ICH guideline for Analytical Procedures 6 . Recent studies suggested that protease inhibitors like Darunavir, Ritonavir, Nelfinavir showed no evidence of antagonism when used with TMC114 7,8 . Literature survey reveals that there are reports describing the determination of Darunavir in Plasma using liquid chromatography coupled with Tandem Mass Spectroscopy 9 , few HPTLC method for determination of Darunavir in rat plasma and in tablet dosage form its application to pharmacokinetic studies 10,11 , infrared spectroscopy method for determination of Darunavir in tablets 12 , and few RP-HPLC and Spectrophotometric methods 13,14 .…”

Studies of continuous-flow synthesis of nonpeptidal bistetrahydrofuran moiety of Darunavir

“…The future management of HIV/AIDS should rely upon the development of therapies that are less toxic and more effective in combating drugresistance. 1 In this context, the Darunavir have enjoyed a surge in popularity as a new generation of PIs bearing a structure-based designed bis-THF ligand that effectively fills in the hydrophobic pocket and maximizes hydrogen bonding interactions with the backbone atoms of the S2-site.…”

Studies on the Continuous-Flow Synthesis of Nonpeptidal bis-Tetrahydrofuran Moiety of Darunavir

“…Several reviews describe the benefits of applying continuous-flow methods in organic synthesis, including better mixing, efficient mass and heat transfer, and the ability to readily scale-up a given flow process by applying numbering-up or scaling-out principles [1,2]. A particularly challenging area in flow chemistry is the synthesis of active pharmaceutical ingredients (APIs), which typically involves a significant number of synthetic steps, and is therefore clearly a rather complex operation [6]. Recently, our group demonstrated the advantages of continuous-flow chemistry in the synthesis of important HIV protease inhibitor building blocks, such as Atazanavir.…”

“…Its high potency allows its use as a rescue drug in patients where standard treatment fails. Structurally, Darunavir (1) bears a (3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-ol core which fills the hydrophobic pocket of the HIV protease and maximizes hydrogen bonding interactions with the backbone atoms of the active site [6].…”