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At least 19 recordsLinked to original sources
PubMed2007

Pharmacokinetic interaction between darunavir boosted with ritonavir and omeprazole or ranitidine in human immunodeficiency virus-negative healthy volunteers.

Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.

Adolescent↗
PubMed2006

Darunavir (Prezista) for HIV infection.

Darunavir (Prezista--Tibotec), a new protease inhibitor, has received accelerated approval from the FDA for use in combination therapy of human-immunodeficiency-virus (HIV) infection in previously treated adults. It is coadministered with low-dose ritonavir (Norvir), which increases its bioavailability.

Antiretroviral Therapy, Highly Active↗
PubMedDate not supplied

Prezista (darunavir, TMC-114) approved; may be important treatment advance.

A major new antiretroviral has been approved, for patients resistant to more than one protease inhibitor. There is no information yet on risk/benefit compared to standard treatments for first-line use. Tibotec, which developed the drug and is now part of Johnson & Johnson, showed price restraint and avoided setting a new record high price, which other companies have done.

Darunavir↗
PubMed2006

Screening and selecting for optimized antiretroviral drugs: rising to the challenge of drug resistance.

BACKGROUND: Resistance to antiretroviral (ARV) drugs constitutes one of the greatest limitations to effective long-term therapy for human immunodeficiency virus (HIV) infection--a problem alleviated, but by no means overcome, by the application of carefully selected, sequential combination regimens. The rational development of novel therapeutics with the ability to suppress viraemia effectively and also address the complex problems of resistance offers a useful way forward for HIV therapy. The investigational drug TMC114 (darunavir) was designed to be active against both wild-type HIV and strains that are resistant to currently available protease inhibitors. SCOPE: This review describes the challenges posed by HIV drug resistance and the novel approach taken in the design and selection of TMC114. Articles were identified by searching MEDLINE in September 2005 (search limits: 1995-2006) using the terms: TMC114, darunavir, resistance, screening, selection, ARV therapy, HIV and HAART. Additional data included bibliographies from identified articles. FINDINGS: With the continuing problem of resistance, ARV drugs must be designed with broad-spectrum activity forming a central part of their development and screening. Drugs must not only be able to treat existing resistant strains, but must also possess more intrinsic resilience to the development of resistance. TMC114 was designed and selected with strong emphasis on potent activity across a range of both wild-type and resistant HIV strains and high binding affinity to HIV protease. CONCLUSION: This review illustrates that future treatment strategies should include screening against multiple-resistant strains to optimize the identification of novel therapeutic agents for the treatment of HIV.

Anti-HIV Agents↗
PubMed2006

Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114.

TMC114 (darunavir) is a promising clinical inhibitor of HIV-1 protease (PR) for treatment of drug resistant HIV/AIDS. We report the ultra-high 0.84 A resolution crystal structure of the TMC114 complex with PR containing the drug-resistant mutation V32I (PR(V32I)), and the 1.22 A resolution structure of a complex with PR(M46L). These structures show TMC114 bound at two distinct sites, one in the active-site cavity and the second on the surface of one of the flexible flaps in the PR dimer. Remarkably, TMC114 binds at these two sites simultaneously in two diastereomers related by inversion of the sulfonamide nitrogen. Moreover, the flap site is shaped to accommodate the diastereomer with the S-enantiomeric nitrogen rather than the one with the R-enantiomeric nitrogen. The existence of the second binding site and two diastereomers suggest a mechanism for the high effectiveness of TMC114 on drug-resistant HIV and the potential design of new inhibitors.

Amino Acid Substitution↗
PubMed2006

Etravirine: R165335, TMC 125, TMC-125, TMC125.

Etravirine [TMC 125] is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is being developed by Tibotec (Tibotec-Virco Group; now Johnson & Johnson) for the treatment of HIV-1 infections. Etravirine is a highly flexible, di-aryl-pyrimidine (DAPY) compound. The flexibility enables favourable binding interactions with mutant HIV strains as well as wild-type virus. Etravirine has superseded dapivirine as Tibotec's lead NNRTI in clinical development worldwide. Tibotec merged with Virco to form Tibotec-Virco Group in March 2001. Subsequently, Tibotec-Virco Group was acquired by Johnson & Johnson on 18 April 2002. Etravirine was discovered by Tibotec in collaboration with the Janssen Research Foundation. However, the Janssen Research Foundation is no longer involved in the development of etravirine. Etravirine has received fast-track status from the US FDA for the treatment of HIV-1 infections. An expanded access programme for etravirine began in the US in September 2006. The programme made etravirine available to HIV-1 infected adults who have limited treatment options due to virological failure or intolerance to multiple antiretroviral regimens. The progamme will also be introduced in Canada and Europe. In November 2005, Tibotec initiated two randomised, placebo-controlled phase III trials of etravirine in treatment-experienced HIV-1 infected patients with NNRTI resistance and at least three primary protease mutations. The two trials will each enroll 600 patients and will be conducted in 18 countries. Darunavir will be used as the background protease inhibitor in the trials. This is the first time that two investigational antivirals have been evaluated in combination in heavily treatment-experienced patients. The trial design is supported by the FDA, the Committee for Medicinal Products for Human Use (CHMP) of the EMEA and the HIV patient community. Patient enrolment in the two phase III trials was completed in September 2006. A multicentre phase IIb dose-finding study (TMC125 C223) in Europe, Canada and the US found etravirine significantly reduced the HIV viral load in a subset of heavily treatment-experienced patients. Tibotec discontinued a single exploratory open-label phase II trial (TMC 125-C227) of etravirine in November 2005. The discontinuation was a result of 12-week data, which demonstrated a difference in the proportion of patients achieving or maintaining undetectable viral load in favour of the control group, who were receiving protease inhibitor-based treatment. There were no safety concerns and the discontinuation had no effect on phase III registration trials. Phase IIa clinical trials of etravirine for the treatment of HIV infections, initiated in November 2001, have been completed. Tibotec has conducted a phase I trial (TMC125-C157 study) evaluating etravirine + didanosine among healthy volunteers in Belgium; trial results have been presented.

Administration, Oral↗
PubMed2004

Gateways to clinical trials.

Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 166Ho-DOTMP 5A8; A-179578, abetimus sodium, adefovir dipivoxil, AGI-1067, AIDSVAX gp120 B/B, AK-602, alefacept alemtuzumab, aliskiren fumarate, ALVAC vCP1433, ALVAC vCP1452, anecortave acetate, arzoxifene hydrochloride, atazanavir sulfate, atlizumab, avasimibe; Binodenoson, BMS-488043; Choriogonadotropin alfa, ciclesonide, COL-1621, CVT-3146, CVT-E002, Cypher; Daptomycin, darbepoetin alfa, darunavir, D-D4FC, deferasirox, desloratadine, desmoteplase, duloxetine hydrochloride, DX-9065a; E-5564, efalizumab, emfilermin, emivirine, emtricitabine, enfuvirtide, estradiol acetate, ezetimibe; Frovatriptan; Gallium maltolate, gefitinib; HIV-1 Immunogen, human insulin; Iguratimod, IL-4/IL-13 Trap, imatinib mesylate, inhaled insulin, insulin glargine, irofulven, ISS-1018, ivabradine hydrochloride; Lutropin alfa; Melatonin; Nesiritide; O6-Benzylguanine, omapatrilat, oritavancin, ospemifene; Parecoxib sodium, peginterferon alfa-2a, pexelizumab, pimecrolimus, pirfenidone, pramlintide acetate, prasterone sulfate PT-141; Rasburicase, razaxaban hydrochloride, recombinant malaria vaccine, rhBMP-2/ACS, roflumilast, rosiglitazone maleate/metformin hydrochloride, rotavirus vaccine; SCH-D, sitaxsentan sodium, solifenacin succinate; Targinine hydrochloride, taxus, TER-199, tramadol hydrochloride/acetaminophen; Valdecoxib, valganciclovir hydrochloride, vatalanib succinate, VEG Trap(R1R2); Ximelagatran; Yttrium Y90 Epratuzumab.

Clinical Trials as Topic↗
PubMed2005

Development of a capillary electrophoretic method for the separation of diastereoisomers of a new human immunodeficiency virus protease inhibitor.

A capillary electrophoretic (CE) method was developed for the separation of diastereoisomers of a new human immunodeficiency virus (HIV) protease inhibitor TMC114. In total 16 isomers of this drug have been synthesized (eight pairs of enantiomers). We succeeded in the separation of the eight diastereoisomers, but no enantiomers could be separated. Because of the high similarity and water-insolubility of these isomers, the separation is a real challenge. Different CE modes were tried out: capillary zone electrophoresis (CZE), nonaqueous capillary electrophoresis (NACE), micellar electrokinetic capillary chromatography (MEKC), and microemulsion electrokinetic capillary chromatography (MEEKC). Only MEEKC offered resolution of these compounds.

Acetonitriles↗
PubMed2004

High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains.

The compound UIC-94017 (TMC-114) is a second-generation HIV protease inhibitor with improved pharmacokinetics that is chemically related to the clinical inhibitor amprenavir. UIC-94017 is a broad-spectrum potent inhibitor active against HIV-1 clinical isolates with minimal cytotoxicity. We have determined the high-resolution crystal structures of UIC-94017 in complexes with wild-type HIV-1 protease (PR) and mutant proteases PR(V82A) and PR(I84V) that are common in drug-resistant HIV. The structures were refined at resolutions of 1.10-1.53A. The crystal structures of PR and PR(I84V) with UIC-94017 ternary complexes show that the inhibitor binds to the protease in two overlapping positions, while the PR(V82A) complex had one ordered inhibitor. In all three structures, UIC-94017 forms hydrogen bonds with the conserved main-chain atoms of Asp29 and Asp30 of the protease. These interactions are proposed to be critical for the potency of this compound against HIV isolates that are resistant to multiple protease inhibitors. Other small differences were observed in the interactions of the mutants with UIC-94017 as compared to PR. PR(V82A) showed differences in the position of the main-chain atoms of residue 82 compared to PR structure that better accommodated the inhibitor. Finally, the 1.10A resolution structure of PR(V82A) with UIC-94017 showed an unusual distribution of electron density for the catalytic aspartate residues, which is discussed in relation to the reaction mechanism.

Aspartic Acid↗
PubMed2005

Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor.

The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high enthalpy driven affinity of TMC114 for HIV-1 protease. In vitro selection of mutants resistant to TMC114 starting from wild-type virus proved to be extremely difficult; this was not the case for other close analogues. Therefore, the extra H-bond to the backbone in the P2 pocket cannot be the only explanation for the interesting antiviral profile of TMC114. Absorption studies in animals indicated that TMC114 has pharmacokinetic properties comparable to currently approved HIV-1 protease inhibitors.

Administration, Oral↗
PubMed2006

Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M.

The potent new antiviral inhibitor TMC-114 (UIC-94017) of HIV-1 protease (PR) has been studied with three PR variants containing single mutations D30N, I50V, and L90M, which provide resistance to the major clinical inhibitors. The inhibition constants (K(i)) of TMC-114 for mutants PR(D30N), PR(I50V), and PR(L90M) were 30-, 9-, and 0.14-fold, respectively, relative to wild-type PR. The molecular basis for the inhibition was analyzed using high-resolution (1.22-1.45 A) crystal structures of PR mutant complexes with TMC-114. In PR(D30N), the inhibitor has a water-mediated interaction with the side chain of Asn30 rather than the direct interaction observed in PR, which is consistent with the relative inhibition. Similarly, in PR(I50V) the inhibitor loses favorable hydrophobic interactions with the side chain of Val50. TMC-114 has additional van der Waals contacts in PR(L90M) structure compared to the PR structure, leading to a tighter binding of the inhibitor. The observed changes in PR structure and activity are discussed in relation to the potential for development of resistant mutants on exposure to TMC-114.

Crystallization↗
PubMed2006

Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance.

Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 A resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed2004

Stereoselective photochemical 1,3-dioxolane addition to 5-alkoxymethyl-2(5H)-furanone: synthesis of bis-tetrahydrofuranyl ligand for HIV protease inhibitor UIC-94017 (TMC-114).

A convenient synthesis of (3R,3aS,6aR)-3-hydroxyhexahydrofuro[2,3-b]furan, a high-affinity nonpeptidal ligand for HIV protease inhibitor UIC-94017, is described. This inhibitor is undergoing advanced clinical trials. The synthesis utilizes a novel stereoselective photochemical 1,3-dioxolane addition to 5(S)-benzyloxymethyl-2(5H)-furanone as the key step. The requisite furanone derivative was prepared in high enantiomeric excess by an immobilized lipase-catalyzed selective acylation of (+/-)-1-(benzyloxy)-3-buten-2-ol and a ring-closing olefin metathesis with Grubbs' catalyst. Optically active bis-THF was converted to protease inhibitor 2 (UIC-94017).

Catalysis↗
PubMed2005

Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol.

[reaction: see text] Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O-isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.

Cyclization↗