Darunavir - CAS 206361-99-1
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Not Intended for Therapeutic Use. For research use only.
Darunavir is a second generation protease inhibitor that targets the HIV-1 protease. It demonstrates extremely potent activity against the infectivity and replication of various strains of HIV-1, including several that are resistant to first generation protease inhibitors (IC50s = 3-30 nM). Darunavir has been reported to inhibit both cell-free diffusion and cell-to-cell spread of HIV-1 with IC50 values of 2.5 and 2.8 nM, respectively
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Prezista,TMC114, [(1R,5S,6R)-2,8-dioxabicyclo[3.3.0]oct-6-yl] N-[(2S,3R)-4- [(4-aminophenyl)sulfonyl- (2-methylpropyl)amino]-3-hydroxy-1-phenyl- butan-2-yl] carbamate
1. Discovery of GS-8374, a potent human immunodeficiency virus type 1 protease inhibitor with a superior resistance profile
Gong-Xing He, Zheng-Yu Yang, Med. Chem. Commun., 2011, 2, 1093
Boosting of PIs with low-dose RTV is now widely used to achieve desirable drug plasma concentrations, which lead to improved viral suppression while decreasing both the dosing frequency and pill burden. Current HIV treatment guidelines recommend ritonavir-boosted atazanavir (ATV) or darunavir (DRV) as a third agent of choice for first line antiretroviral therapy. Although there are nine PIs currently licensed for the treatment of HIV-1, and new generation PIs show better pharmacological properties than the earlier agents, profiles of most of the currently approved PIs can be further improved. The clinical benefit of this class of anti-retrovirals in general is still limited by several factors including resistance and long-term safety and tolerability. Among these, the emergence of drug-resistant HIV-1 variants continues to be a major cause of treatment failure and presents a major challenge to the control of HIV infection. In addition, withthe exception of ATV, other PIs require high dose and/or frequent dosing regi- mens, limiting their use in fixed dose combination regimens. Therefore, the design of novel PIs with more favorable resistance profiles and convenient dosing regimens remains a consistent interest in the scientific community. This communication describes the discovery and characteristics of GS-8374 (compound 1, Fig. 1), a potent and orally bioavailable PI with a superior resistance profile against a spectrum of patient-derived HIV-1 variants highly resistant to multiple PIs.
2. Stability-indicating thin-layer chromatographic method for determination of darunavir in complex darunavir–b-cyclodextrin in the presence of its degradation products
Ana Carolina Kogawa,* Jaqueline Nakau Mendonça, Norberto Peporine Lopes and Herida Regina Nunes Salgadoa. Anal. Methods,2014, 6,3689–3693
Darunavir (DRV), a protease inhibitor used in the treatment of HIV infection, is a new generation of synthetic non-peptidic protease inhibitors, a vital part of the therapy cocktail given to patients with the virus. Its chemical structure is shown in Fig. 1. Darunavir (DRV) presents low water solubility and poor bioavailability; therefore, the complexation of Darunavir (DRV) to b-cyclodextrin was performed. The b-CD is an excipient and has been used in the development of pharmaceuticals, particularly because of its complexing properties, which provide increased solubility and consequent increase in the rate of dissolution of poorly soluble drugs.
3. Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands
Arun K. Ghosh,* Cuthbert D. Martyr, Luke A. Kassekert. Org. Biomol. Chem.,2015, 13, 11607–11621
In order to obtain molecular insight into the HIV-1 protease–inhibitor interactions, we have determined X-ray structures of HIV-1 protease complexed with compounds 30b and 30j. A stereoview of 30b-bound HIV-1 protease structure is shown in Fig. 2. The crystal structure of wild type HIV-1 protease with inhibitor 30b was determined and refined at 1.22 Å resolution. This crystal structure contains the protease dimer and the inhibitor bound in two orientations related by a 180° rotation with 55/45% relative occupancies. The overall structure is similar to the structure of HIV-1 protease with darunavir with root mean square differences of 0.13 Å for Cα atoms. Inhibitor 30b has a tetrahydropyrano-tetrahydrofuran (Tp-THF) group at P2, which bears a methoxy group. The Tp-THF ring shows a slight bend compared to the complex with the related bis-THF inhibitor bis-THF derived (pdb code: 3QAA). As shown, the methoxy group on the Tp-THF ligand forms a water-mediated interaction with the amide NH of Gly48. These interactions likely stabilize the flexible flap region of the active site cavity. The new interactions with the flap region may be responsible for its robust antiviral activity.
4. Drug resistance mechanisms of three mutations V32I, I47V and V82I in HIV-1 protease toward inhibitors probed by molecular dynamics simulations and binding free energy predictions
Jianzhong Chen. RSC Adv.,2016, 6,58573–58585
All-atom MD simulations not only provide dynamical details of atom fluctuations, but also contribute important information on interactions of ligands with proteins by using post-process analysis based on MD trajectories. The calculated simulations have also got success in investigating drug resistance of mutations toward PIs. To obtain deeper insight into drug-resistant mechanism of three mutations V32I, I47V and V82I toward PIs, three PIs saquinavir (SQV), amprenavir (APV) and darunavir (DRV) were selected and their structures were shown in Fig. 1B–D. SQV is the first-generation PI approved by FDAwith a Ki value of 0.11 nM (Fig. 1B). Compared with SQV, the structure of APV contains a sulfonamide and a hydroxyethylamine, and it produces potent inhibition ability on PR with a Ki value of 0.15 nM (Fig. 1C). DRV is a new-generation potent PI and its Ki value reaches 0.04 nM (Fig. 1D). Three mutations V32I, I47V and V82I generate different-level drug resistance on the three current selected inhibitors. In this work, MD simulations, binding free energy calculations and dynamical analyses were combined to probe drug-resistantmechanismof three mutations toward inhibitors.
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CAS 206361-99-1 Darunavir

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