scholarly journals ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

1998 ◽  
Vol 42 (12) ◽  
pp. 3218-3224 ◽  
Author(s):  
Hing L. Sham ◽  
Dale J. Kempf ◽  
Akhteruzammen Molla ◽  
Kennan C. Marsh ◽  
Gondi N. Kumar ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Response To Therapy ◽  
Hiv Protease ◽  
Healthy Human ◽  
Human Volunteers ◽  
Immunodeficiency Virus ◽  
Potent Protease Inhibitor

ABSTRACT The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 μM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, ≤0.06 μM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

scholarly journals Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Type 1 Protease Inhibitor, following Repeat Administration with and without Ritonavir in Healthy Adult Subjects

2007 ◽  
Vol 51 (4) ◽  
pp. 1202-1208 ◽  
Author(s):  
Y. Sunila Reddy ◽  
Susan L. Ford ◽  
Maggie T. Anderson ◽  
Sharon C. Murray ◽  
Judith Ng-Cashin ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Geometric Mean ◽  
Repeat Dose ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Immunodeficiency Virus ◽  
Potent Protease Inhibitor ◽  
Hiv 1

ABSTRACT Brecanavir (BCV) is a novel, potent protease inhibitor in development for the treatment of human immunodeficiency virus (HIV-1) infection with low nM in vitro 50% inhibitory concentrations (IC50s) against many multiprotease inhibitor resistant viruses. This study was a double-blind, randomized, placebo-controlled repeat-dose escalation to evaluate the safety, tolerability, and pharmacokinetics of BCV, with or without ritonavir (RTV), in 68 healthy subjects. Seven sequential cohorts (n = 10) received BCV (50 to 600 mg) in combination with 100 mg RTV (every 12 h [q12h] or q24h) or alone at 800 mg q12h for 15 days. BCV alone or in combination with RTV was well tolerated, with no serious adverse events reported. The most common drug-related adverse event was headache. BCV was readily absorbed with median time to maximum concentration of drug in serum values ranging from 2.5 to 5.0 h postdose following single- and repeat-dose administration of BCV alone and BCV with RTV 100 mg. Geometric mean BCV accumulation ratios ranged from 1.4 to 1.56 following BCV-RTV q24h regimens and from 1.84 to 4.93 following BCV q12h regimens. BCV steady state was generally achieved by day 13 in all groups. All day 15 BCV-RTV trough concentration values in q12h regimens reached or surpassed the estimated protein-binding corrected in vitro IC50 target BCV concentration of 28 ng/ml for highly resistant isolates. The pharmacokinetic and safety profile of BCV-RTV supports continued investigation in HIV-1-infected subjects.

scholarly journals In vitro anti-human immunodeficiency virus (HIV) activity of XM323, a novel HIV protease inhibitor.

1993 ◽  
Vol 37 (12) ◽  
pp. 2606-2611 ◽  
Author(s):  
M J Otto ◽  
C D Reid ◽  
S Garber ◽  
P Y Lam ◽  
H Scarnati ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Hiv Protease ◽  
Hiv Protease Inhibitor ◽  
Immunodeficiency Virus

scholarly journals A Novel Bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI), GRL-98065, Is Potent against Multiple-PI-Resistant Human Immunodeficiency Virus In Vitro

2007 ◽  
Vol 51 (6) ◽  
pp. 2143-2155 ◽  
Author(s):  
Masayuki Amano ◽  
Yasuhiro Koh ◽  
Debananda Das ◽  
Jianfeng Li ◽  
Sofiya Leschenko ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Close Contact ◽  
Wide Spectrum ◽  
Antiviral Agents ◽  
Cyclic Ether ◽  
Hiv Protease ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF), and a sulfonamide isostere, which is highly potent against laboratory HIV-1 strains and primary clinical isolates (50% effective concentration [EC50], 0.0002 to 0.0005 μM) with minimal cytotoxicity (50% cytotoxicity, 35.7 μM in CD4+ MT-2 cells). GRL-98065 blocked the infectivity and replication of each of the HIV-1NL4-3 variants exposed to and selected by up to a 5 μM concentration of saquinavir, indinavir, nelfinavir, or ritonavir and a 1 μM concentration of lopinavir or atazanavir (EC50, 0.0015 to 0.0075 μM), although it was less active against HIV-1NL4-3 selected by amprenavir (EC50, 0.032 μM). GRL-98065 was also potent against multiple-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents, HIV-1 isolates of various subtypes, and HIV-2 isolates examined. Structural analyses revealed that the close contact of GRL-98065 with the main chain of the protease active-site amino acids (Asp29 and Asp30) is important for its potency and wide-spectrum activity against multiple-PI-resistant HIV-1 variants. The present data demonstrate that the privileged nonpeptide P2 ligand, bis-THF, is critical for the binding of GRL-98065 to the HIV protease substrate binding site and that this scaffold can confer highly potent antiviral activity against a wide spectrum of HIV isolates.

scholarly journals 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1997 ◽  
Vol 41 (5) ◽  
pp. 1082-1093 ◽  
Author(s):  
S M Daluge ◽  
S S Good ◽  
M B Faletto ◽  
W H Miller ◽  
M H St Clair ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Bioavailability ◽  
Human Peripheral Blood ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Carbocyclic Nucleoside ◽  
Hiv 1 ◽  
In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

scholarly journals Novel bis-Tetrahydrofuranylurethane-Containing Nonpeptidic Protease Inhibitor (PI) UIC-94017 (TMC114) with Potent Activity against Multi-PI-Resistant Human Immunodeficiency Virus In Vitro

2003 ◽  
Vol 47 (10) ◽  
pp. 3123-3129 ◽  
Author(s):  
Yasuhiro Koh ◽  
Hirotomo Nakata ◽  
Kenji Maeda ◽  
Hiromi Ogata ◽  
Geoffrey Bilcer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Therapeutic Agent ◽  
Close Contact ◽  
Wide Spectrum ◽  
Antiviral Agents ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT We designed, synthesized, and identified UIC-94017 (TMC114), a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing a 3(R),3a(S),6a(R)-bis-tetrahydrofuranylurethane (bis-THF) and a sulfonamide isostere which is extremely potent against laboratory HIV-1 strains and primary clinical isolates (50% inhibitory concentration [IC50], ∼0.003 μM; IC90, ∼0.009 μM) with minimal cytotoxicity (50% cytotoxic concentration for CD4+ MT-2 cells, 74 μM). UIC-94017 blocked the infectivity and replication of each of HIV-1NL4-3 variants exposed to and selected for resistance to saquinavir, indinavir, nelfinavir, or ritonavir at concentrations up to 5 μM (IC50s, 0.003 to 0.029 μM), although it was less active against HIV-1NL4-3 variants selected for resistance to amprenavir (IC50, 0.22 μM). UIC-94017 was also potent against multi-PI-resistant clinical HIV-1 variants isolated from patients who had no response to existing antiviral regimens after having received a variety of antiviral agents. Structural analyses revealed that the close contact of UIC-94017 with the main chains of the protease active-site amino acids (Asp-29 and Asp-30) is important for its potency and wide spectrum of activity against multi-PI-resistant HIV-1 variants. Considering the favorable pharmacokinetics of UIC-94017 when administered with ritonavir, the present data warrant that UIC-94017 be further developed as a potential therapeutic agent for the treatment of primary and multi-PI-resistant HIV-1 infections.

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