Viracept (Nelfinavir Mesylate, AG1343):  A Potent, Orally Bioavailable Inhibitor of HIV-1 Protease

1997 ◽  
Vol 40 (24) ◽  
pp. 3979-3985 ◽  
Author(s):  
Stephen W. Kaldor ◽  
Vincent J. Kalish ◽  
Jay F. Davies ◽  
Bhasker V. Shetty ◽  
James E. Fritz ◽  
...  
Keyword(s):  
Nelfinavir Mesylate ◽  
Orally Bioavailable ◽  
Hiv 1

scholarly journals Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease.

1996 ◽  
Vol 40 (2) ◽  
pp. 292-297 ◽  
Author(s):  
A K Patick ◽  
H Mo ◽  
M Markowitz ◽  
K Appelt ◽  
B Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Methanesulfonic Acid ◽  
Serial Passage ◽  
Proteolytic Processing ◽  
Hiv Protease ◽  
Structure Based Drug Design ◽  
Recombinant Viruses ◽  
Immunodeficiency Virus ◽  
Orally Bioavailable ◽  
Hiv 1

AG1343 ([3S-(3R*,4aR*,8aR*,2'S*,3'S*)]-2-[2' hydroxy-3'-phenylthiomethyl-4'-aza-5'-oxo-5'-(2''-methyl-3''-hydro xy-phenyl) pentyl]-decahydroiso-quinoline-3-N-t-butylcarboxamide methanesulfonic acid) is a selective, nonpeptidic inhibitor of human immunodeficiency virus (HIV) protease (Ki = 2 nM) that was discovered by protein structure-based drug design methodologies. AG1343 was effective against the replication of several laboratory and clinical HIV type 1 (HIV-1) or HIV-2 isolates including pyridinone- and zidovudine-resistant strains, with 50% effective concentrations ranging from 9 to 60 nM. In reversibility studies, inhibition of gag (p55) proteolytic processing in HIV-1 particles from cells treated with AG1343 was maintained for up to 36 h after drug removal. The ability of virus to develop resistance to AG1343 was studied by serial passage of HIV-1 NL4.3 in the presence of increasing concentrations of drug. After 28 passages, a variant with a 30-fold reduction in susceptibility to AG1343 was isolated. Molecular analysis of the protease from this variant indicated a double change from a Met to Ile at residue 46 and an Ile to Val or Ala at residue 84 (M46I+I84V, A). Consistent with these findings, reductions in susceptibility were observed for recombinant viruses constructed to contain the single I84V change or the double M46I+I84V substitutions. Resistance, however, was not detected for recombinant viruses containing other key mutations in HIV-1 protease, including a Val to Ile change at residue 32 or a Val to Ala or Phe at residue 82. The potent anti-HIV activity of AG1343 against several isolates suggests that AG1343 should perform well during ongoing human phase II clinical trials.

New Series of Potent, Orally Bioavailable, Non-Peptidic Cyclic Sulfones as HIV-1 Protease Inhibitors

1996 ◽  
Vol 39 (18) ◽  
pp. 3431-3434 ◽  
Author(s):  
Choung U. Kim ◽  
Lawrence R. McGee ◽  
Steven H. Krawczyk ◽  
Erik Harwood ◽  
Yoko Harada ◽  
...  
Keyword(s):  
Protease Inhibitors ◽  
Orally Bioavailable ◽  
Hiv 1

Antiretroviral agents: Focus on Maraviroc for the Treatment of HIV-1-Infected Adults

2010 ◽  
Vol 2 ◽  
pp. CMT.S5420
Author(s):  
SL. Pett ◽  
S. Emery ◽  
AD. Kelleher ◽  
DA. Cooper
Keyword(s):  
Hiv Infection ◽  
Chemokine Receptors ◽  
Hiv Transmission ◽  
Hiv Therapy ◽  
Ccr5 Receptor ◽  
Tick Borne Encephalitis ◽  
Hiv Entry ◽  
Orally Bioavailable ◽  
Hiv Envelope ◽  
Hiv 1

Over a decade has passed since several groups identified the chemokine receptors CXCR4 and CCR5 as key co-receptors for HIV entry. CCR5 is more important in HIV transmission and during the early course of HIV infection. It is also apparent that protection from HIV infection is afforded to those lacking CCR5–-the so called delta-32 homozygotes; in those heterozygous for this mutation, an attenuated course of HIV-infection is observed. Provocatively, those with modified expression of CCR5 are physiologically normal with the exception of poorer outcomes with some of the viral encephalitides specifically West Nile virus and Tick Borne encephalitis. The small molecule, orally-bioavailable CCR5 receptor antagonists, including, maraviroc (MVC), are allosteric inhibitors that lock the CCR5 receptor into a conformation such that the receptor is not able to bind HIV envelope protein; the molecules also variably block intracellular signalling induced by different receptor-binding chemokines. The aims of this review on the CCR5 receptor inhibitors are to summarise information relevant to treatment in individuals with HIV-1 infection. Data from the licensing studies, the side-effect profile and putative long-term risks of CCR5 receptor inhibitor exposure, tropism testing and mechanisms of resistance will be reviewed. The potential for using this class of agent as an immunomodulating agent will be detailed. Given that MVC is the only licensed drug in this class at present and reflecting the greater body of work describing this agent, the majority of information in this review relates to MVC. Last, the authors propose the place of MVC in the hierarchy of HIV therapy and future opportunities for research.

scholarly journals Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

1997 ◽  
Vol 41 (10) ◽  
pp. 2159-2164 ◽  
Author(s):  
A K Patick ◽  
T J Boritzki ◽  
L A Bloom
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitors ◽  
Drug Combination ◽  
Cellular Cytotoxicity ◽  
Immunodeficiency Virus ◽  
Nelfinavir Mesylate ◽  
Acute Hiv ◽  
Hiv 1

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme

1995 ◽  
Vol 117 (3) ◽  
pp. 1181-1182 ◽  
Author(s):  
E. E. Kim ◽  
C. T. Baker ◽  
M. D. Dwyer ◽  
M. A. Murcko ◽  
B. G. Rao ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Orally Bioavailable ◽  
Hiv 1

Inhibitors of HIV-1 attachment. Part 7: Indole-7-carboxamides as potent and orally bioavailable antiviral agents

2013 ◽  
Vol 23 (1) ◽  
pp. 198-202 ◽  
Author(s):  
Kap-Sun Yeung ◽  
Zhilei Qiu ◽  
Quifen Xue ◽  
Haiquan Fang ◽  
Zheng Yang ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Orally Bioavailable ◽  
Hiv 1

Design and Synthesis of Bicyclic Pyrimidinones as Potent and Orally Bioavailable HIV-1 Integrase Inhibitors

2008 ◽  
Vol 51 (4) ◽  
pp. 861-874 ◽  
Author(s):  
Ester Muraglia ◽  
Olaf Kinzel ◽  
Cristina Gardelli ◽  
Benedetta Crescenzi ◽  
Monica Donghi ◽  
...  
Keyword(s):  
Integrase Inhibitors ◽  
Design And Synthesis ◽  
Orally Bioavailable ◽  
Hiv 1
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