Benzocycloalkyl amines as novel C-termini for HIV protease inhibitors

Lyle, Terry A.; Wiscount, Catherine M.; Guare, James P.; Thompson, Wayne J.; Anderson, Paul S.; Darke, Paul L.; Zugay, Joan A.; Emini, Emilio A.; Schleif, William A.

doi:10.1021/jm00107a051

Cited by 100 publications

(37 citation statements)

References 5 publications

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“…Because many of the peptidic substrates and inhibitors of HIV-1 PRs are sparingly soluble in aqueous solutions, DMSO is widely used as a solvent for concentrated stock solutions [15,[24][25][26][27]. This can result in concentrations of DMSO in the final assay mixtures as high as 10% (v/v) [25,26].…”

Section: Inhibition By Dmsomentioning

confidence: 99%

Kinetic properties of HIV-1 protease produced by total chemical synthesis with cysteine residues replaced by isosteric L-?-amino-n-butyric acid

Bergman

Alewood

et al. 1995

Lett Pept Sci

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Human immunodeficiency virus-I protease, produced by total chemical synthesis with the cysteine residues replaced by L-a-amino-n-butyric acid ([Aba 67' 95] HIV-1 PR), has been used extensively for the X-ray crystallographic structural analysis of the enzyme and its complexes utilized in drug design. Here we report kinetic studies on the synthetic enzyme. The pH optimum is 5.5 at ionic strengths of 0.1 and 1.0. The acid pH optimum is due to a decrease in binding affinity at higher pH values rather than to a reduction in catalytic efficiency. Activity is markedly increased by high ionic strength, although the major effect is on Km and not kca t. The effect of pH and ionic strength on the kinetic constants determined for substrates and inhibitors is demonstrated and attention is drawn to the need for assay conditions to be explicitly reported in studies on inhibitor activity. The effect of a number of inhibitors has been measured against the synthetic enzyme and a recombinant HIV-1 PR. This work shows that [Aba 67' 95] HIV-1 PR has full enzymatic activity and normal kinetic properties.

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Section: Inhibition By Dmsomentioning

confidence: 99%

Kinetic properties of HIV-1 protease produced by total chemical synthesis with cysteine residues replaced by isosteric L-?-amino-n-butyric acid

Bergman

Alewood

et al. 1995

Lett Pept Sci

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“…This hydroxyl group is likely to make three hydrogen bonds; two with the main-chain NH of Asp TM and Asp 3°' and one with either the side-chain oxygen or the main-chain carbonyl of Asp 3°'. In a different class of inhibitors, a hydroxyl group attached to the P2' group contributes an increase in binding of about 60-fold [5]. The smaller increase in binding of II over II1 appears to suggest a weaker hydrogen-bond interaction between the hydroxyl of II and the enzyme active site.…”

Section: Introductionmentioning

confidence: 97%

Calculation of solvation and binding free energy differences between VX-478 and its analogs by free energy perturbation and AMSOL methods

Rao

Kim

Murcko

1996

J Computer-Aided Mol Des

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VX-478 belongs to a novel class of HIV-1 protease inhibitors that are based on N,N-disubstituted benzene sulfonamides. Force field parameters for the N,N-dialkyl benzene sulfonamide moiety have been assembled from the literature and from our own ab initio calculations. These parameters were employed to calculate solvation and binding free energy differences between VX-478 and two analogs. The free energy perturbation method has been used to determine these differences using two approaches. In the first approach, intergroup interaction terms only were included in the calculation of free energies (as in most reports of free energy calculations using AMBER). In the second approach, both the inter- and intragroup interaction terms were included. The results obtained with the two approaches are in excellent agreement with each other and are also in close agreement with the experimental results. The solvation free energies of N,N-dimethyl benzene sulfonamide derivatives (truncated models of the inhibitors), calculated using continuum solvation (AMSOL) methods, are found to be in qualitative agreement with the experimental and free energy perturbation results. The binding and solvation free energy results are discussed in the context of structure-based drug design to show how physicochemical properties (for example aqueous solubilities and bioavailabilities) of these HIV-I protease inhibitors were improved, while maintaining their inhibitory potency.

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“…Meals high in fat, calories, and protein have a negative effect on IDV's pharmacokinetic profile significantly decreasing the area under the plasma drug concentration-time curve (AUC) (77%) and the maximum plasma concentration of the drug Improve solubility and oral bioavailability Figure 11. Discovery of L-689502-an important lead [11,52,[54][55][56][57]. (C max ) (84%) [59].…”

Section: Pharmacokineticsmentioning

confidence: 99%

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

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Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

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Benzocycloalkyl amines as novel C-termini for HIV protease inhibitors

Cited by 100 publications

References 5 publications

Kinetic properties of HIV-1 protease produced by total chemical synthesis with cysteine residues replaced by isosteric L-?-amino-n-butyric acid

Kinetic properties of HIV-1 protease produced by total chemical synthesis with cysteine residues replaced by isosteric L-?-amino-n-butyric acid

Calculation of solvation and binding free energy differences between VX-478 and its analogs by free energy perturbation and AMSOL methods

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

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