Class Of HIV-1 Protease Inhibitors Research Articles

Isotope labeled ?HEA/HEE? moiety in the synthesis of labeled HIV-protease inhibitors?Part II

[2H5]-Amprenavir and [2H 5]-saquinavir have been prepared from a common labeled precursor (1S, 2S)-(1-oxiranyl-2-[2H5]phenylethyl)-carbamic acid tert-butyl ester, 1. Both of these compounds are in the ‘HEA’ class of HIV protease inhibitors. [2H5]-Indinavir, a representative of the ‘HEE’ group of protease inhibitors, has also been synthesized. In the case of indinavir, 1S-(2,2-dimethyl-8, 8a-dihydro-3aH-indeno-[1,2-d]-oxazol-3R-yl)-2-oxiranylmethyl-3-[2H5]phenylpropan-1-one, 11, provided the [phenyl-2H5]-HEE core structure for synthesis of the desired labeled compound. Copyright © 2005 John Wiley & Sons, Ltd.

Do Non-Nucleoside Reverse Transcriptase Inhibitors Contribute to Lipodystrophy?

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy

Using a newly developed multicomponent chemistry strategy in combination with structure based drug design, a new class of HIV-1 protease inhibitors has been obtained.

Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy

Using a newly developed multicomponent chemistry strategy in combination with structure based drug design, a new class of HIV-1 protease inhibitors has been obtained.

3D-QSAR studies on chromone derivatives as HIV-1 protease inhibitors

The three-dimensional quantitative structure–activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was applied to a series of 30 chromone derivatives, a new class of HIV-1 protease inhibitors. The best predictive CoMFA model gives cross-validated r 2 ( q 2)=0.763, non-cross-validated r 2=0.967, standard error of estimate ( S)=5.092, F=90.701. The best CoMSIA model has q 2=0.707, non-cross-validated r 2=0.943, S=7.018, F=51.734, included steric, electrostatic, hydrophobic, and hydrogen bond donor fields. The predictive ability of these models was validated by a set of five compounds that were not included in the training set. The calculated (predicted) and experimental inhibitory activities were well correlated. The contour maps obtained from CoMFA and CoMSIA models were in agreement with the previous docking study for this chromone series.

Atazanavir: improving the HIV protease inhibitor class

Protease inhibitors are potent agents against HIV but their use is constrained by poor pharmacokinetics, cross-resistance and metabolic toxicities. Atazanavir [Reyataz™] is a new protease inhibitors with once-daily dosing and minimal lipid and glycemic effects. Resistance studies of clinical isolates reveal a mutational pattern distinctive from that of other protease inhibitors. Atazanavir selects for the I50L mutation in HIV protease that confers increased susceptibility to other protease inhibitors in vitro. Clinical trials have shown comparable efficacy to nelfinavir (Viracept®) and efavirenz (Sustiva®) in treatment-naive patients, and in preliminary studies, ritonavir-boosted atazanavir is effective in patients failing previous protease inhibitor-containing regimens. Reversible elevations in bilirubin occur in some patients but are not associated with hepatic injury. Atazanavir improves upon aspects of currently-available protease inhibitors and appears useful for initial and possibly subsequent HIV therapy.

Modeling of Copper(II) Complexes with the SIBFA Polarizable Molecular Mechanics Procedure. Application to a New Class of HIV-1 Protease Inhibitors

We have previously developed a new family of organometallic complexes targeting the HIV-1 protease, an enzyme that is essential for viral maturation. Among these, two Cu2+ complexes C1 and C2 were synthesized from flexible ligands L1, N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide and L2, N2-(2-methoxybenzyl)-2-quinolinecarboxamide, respectively. These ligands, designed to fit the protease active site, were shown to form 2:1 complexes with Cu2+. To compare the relative stability of C1 and C2 and to study the energetic and structural aspects of such large Cu2+ complexes, we have extended the polarizable molecular mechanics procedure SIBFA to treat this cation. This was done by carrying out parallel ab initio (HF, MP2) as well as DFT computations. A first validation step was done on monoligated complexes, in which the SIBFA energy components were shown to correctly match their ab initio counterparts from an energy-decomposition procedure. Subsequent tests on polyligated Cu2+ complexes with neutral and an...

Metabolic complications associated with HIV protease inhibitor therapy.

HIV protease inhibitors were introduced into clinical practice over 7 years ago as an important component of combination antiretroviral drug regimens which in many ways revolutionised the treatment of HIV infection. The significant improvements in prognosis that have resulted from the use of these regimens, combined with the need for lifelong treatment, have increasingly focused attention on the adverse effects of antiretroviral drugs and on the metabolic complications of HIV protease inhibitors in particular. In this review, the cluster of metabolic abnormalities characterised by triglyceride-rich dyslipidaemia and insulin resistance associated with HIV protease inhibitor therapy are considered, along with implications for cardiovascular risk in patients affected by these complications. Toxicity profiles of individual drugs within the HIV protease inhibitor class are examined, as there is an increased recognition of significant intra-class differences both in terms of absolute risk of metabolic complications as well as the particular metabolic phenotype associated with these drugs. Guidelines for clinical assessment and treatment are emphasised, along with pathophysiological mechanisms that may provide a rational basis for the treatment of metabolic complications. Finally, these drug-specific effects are considered within the context of HIV-specific effects on lipid metabolism as well as lifestyle factors that have contributed to a rapidly increasing incidence of similar metabolic syndromes in the general population. These data highlight the importance of individualising patient management in terms of choice of antiretroviral regimen, assessment of metabolic outcomes and use of therapeutic interventions, based on the assessment of baseline (pre-treatment) metabolic status as well as the presence of potentially modifiable cardiovascular risk factors.

ChemInform Abstract: The Process Research and Development of Dupont Merck′s Cyclic Urea Diols, a New Class of HIV Protease Inhibitors

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Itraconazole as an alternative for ritonavir liquid formulation when combined with saquinavir

Itraconazole as an alternative for ritonavir liquid formulation when combined with saquinavir

Cage DimericN-Acyl- andN-Acyloxy-4-aryl-1,4-dihydropyridines as First Representatives of a Novel Class of HIV-1 Protease Inhibitors

The synthesis of a series of novel cage dimeric N-acyl and N-acyloxy-4-aryl-1,4-dihydropyridines starting either from solid-state synthetic ester dimers or from monomeric 4-aryl-1,4-dihydropyridines is presented. Their biological evaluation as novel HIV-1 protease inhibitors showed the most active compounds to be 5c and 5i with inhibitory activities of 52% (50 microM) and 49% (25 microM), respectively. Within each series of N-acyl- and N-acyloxy derivatives NCOBz and NBoc groups were found to be the best substituents. Although they exhibiting only moderate activities these cage dimers hold promise as a class of novel non-peptidic HIV-1 protease inhibitors.

Design of small peptidomimetic HIV-1 protease inhibitors and prodrug forms

The human immunodeficiency virus (HIV) contains an aspartic protease known to be essential for retroviral maturation and replication. Based on the transition state for substrate processing, we designed and synthesized a novel class of HIV-1 protease inhibitors containing an unnatural amino acid, allophenylnorstatine (i.e. (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid), with a hydroxymethylcarbonyl (HMC) isostere. The stereochemistry of the hydroxyl group was important for enzyme inhibition and the HMC group interacted efficiently with the aspartic acid carboxyl groups of the HIV-1 protease active site in essentially the same hydrogen bonding mode as the transition state. Small dipeptide-based HIV-1 protease inhibitors containing the HMC isostere were studied. Since some of these inhibitors showed low solubility in water, we designed a novel class of 'O→N intramolecular acyl migration'-type prodrugs of HIV-1 protease inhibitors for solubilization. Furthermore, we designed and synthesized a novel prodrug-type anti-HIV agent – the conjugate of a peptidomimetic HIV-1 protease inhibitor containing a free carboxylic acid with a nucleoside reverse transcriptase inhibitor. These studies may be useful in anti-HIV drug development.

Increased antiviral activity of cyclic urea HIV protease inhibitors by modifying the P1/P1′ substituents

A series of alkyl substituted P1/P1′ analogs was prepared in an attempt to increase translation of the 3-aminoindazole class of HIV protease inhibitors. Increasing the lipophilicity of the P1/P1′ residues dramatically improved translation of enzyme activity to antiviral activity in the whole cell assay.

Comparison of azacyclic urea A-98881 as HIV-1 protease inhibitor with cage dimeric N-benzyl 4-(4-methoxyphenyl)-1,4-dihydropyridine as representative of a novel class of HIV-1 protease inhibitors: a molecular modeling study.

The functional groups of cage dimeric N-alkyl substituted 3,5-bis(hydroxymethyl)-4-(4-methoxyphenyl)-1,4-dihydropyridines are similar to those of cyclic and azacyclic ureas that are potent inhibitors of HIV-1 protease of the dihydroxyethylene- and hydroxyethylene type, respectively. In the following study the conformity of common functional groups is investigated concerning their orientation in space as well as in the enzyme HIV-1 protease. Starting from X-ray crystal data of the centrosymmetric cage dimeric N-benzyl derivative with ester groups, the derivative with hydroxymethylene groups was built and a systematic conformational search was performed for the conformationally important torsion angles considering electrostatic and van der Waals interactions. From the huge number of conformations those comprising centrosymmetrical and C2-symmetrical energy minima were selected and minimized. The three remaining conformers were fitted to the azacyclic urea A-98881 selected from the HIV-1 protease enzyme-inhibitor complex using the centroids of the corresponding aromatic residues and additionally by the field fit option of the Advanced CoMFA module of SYBYL. Interestingly, the energetically most favourable one, which, additionally, possesses C2-symmetry like the active site cavity of HIV-1 protease, showed the best fit. Comparing the electrostatic potential (EP) of the latter with the EP of A-98881 the aromatic residues show excellent accordance. Slight differences in the extent of the EP were found in the areas of the hydroxymethylene groups of the cage dimer and the single hydroxy group as well as the urea carbonyl group of A-98881, respectively. In order to compare the binding possibilities to the enzyme HIV-1 protease for the cage dimer and A-98881, their interaction fields with certain probes (CH3 for alkyl, NHamide, and carbonyl, O- of COO-), representing the decisive functional groups of the active site, have been calculated using GRID and projected into the enzyme placing the structures according to the position of A-98881 in the enzyme-inhibitor complex. The strongest calculated fields of the O- probe were found near Asp 25 for both structures. Another respective conformity consists in the overlap of the fields for the NHamide probe near Ile 50 and 50' for the investigated cage dimer and A-98881.

Cage dimeric 4-aryl-1,4-dihydropyridines as promising lead structures for the development of a novel class of HIV-1 protease inhibitors.

Cage dimeric 4-aryl-1,4-dihydropyridines as promising lead structures for the development of a novel class of HIV-1 protease inhibitors.

Tricyclic ureas: A new class of HIV-1 protease inhibitors

A new class of tricyclic ureas containing a conformationally constrained proline was designed with the aid of molecular modeling. Efficient stereoselective intermolecular pinacol coupling represented the highlight of the synthesis. These rigid cyclic ureas are active towards HIV-1 protease, with 9 being the most potent compound (Ki = 9 nM) despite interacting with only three side chain binding pockets of HIV protease.

ChemInform Abstract: Synthesis of Unsymmetric Cyclic Urea Diols, a Novel Class of HIV Protease Inhibitors.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of unsymmetric cyclic urea diols, a novel class of HIV protease inhibitors

Unsymmetric cyclic urea diols of general structure 1 can be prepared either via an isourea derived from the symmetric diamine 2 or by the selective removal of a benzyl group from certain symmetric cyclic ureas 8, employing dissolving metal reduction.

KNI-577, a potent small-sized HIV protease inhibitor based on the dipeptide containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.

The development of an effective therapeutic agent for the treatment of AIDS continues to be a challenging problem. Since the discovery that the virally encoded HIV protease is vital for propagation, inhibition of this enzyme has become a major target for AIDS chemotherapy. Consequently, numerous efforts aimed at the development of potent and selective inhibitors have been undertaken[2]. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl (HMC) isostere. Among them, the tripeptide KNI-272 was a highly selective and superpotent HIV protease inhibitor (Ki=5.5 pM)[3]. KNI-272 exhibited potent in vitro and in vivo antiviral activities with low cytotoxicity[4]. The NMR, X-ray crystallography, and molecular modeling studies showed that the HMC group in KNI-272 interacted excellently with the aspartic acid carboxyl groups of the HIV protease active site[5].

Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450

Background: Effective HIV protease inhibitors must combine potency towards wild-type and mutant variants of HIV with oral bioavailability such that drug levels in relevant tissues continuously exceed that required for inhibition of virus replication. Computer-aided design led to the discovery of cyclic urea inhibitors of the HIV protease. We set out to improve the physical properties and oral bioavailability of these compounds. Results: We have synthesized DMP 450 (bis-methanesulfonic acid salt), a water-soluble cyclic urea compound and a potent inhibitor of HIV replication in cell culture that also inhibits variants of HIV with single amino acid substitutions in the protease. DMP 450 is highly selective for HIV protease, consistent with displacement of the retrovirus-specific structural water molecule. Single doses of 10 mg kg −1 DMP 450 result in plasma levels in man in excess of that required to inhibit wild-type and several mutant HIVs. A plasmid-based, in vivo assay model suggests that maintenance of plasma levels of DMP 450 near the antiviral IC 90 suppresses HIV protease activity in the animal. We did identify mutants that are resistant to DMP 450, however; multiple mutations within the protease gene caused a significant reduction in the antiviral response. Conclusions: DMP 450 is a significant advance within the cyclic urea class of HIV protease inhibitors due to its exceptional oral bioavailability. The data presented here suggest that an optimal cyclic urea will provide clinical benefit in treating AIDS if it combines favorable pharmacokinetics with potent activity against not only single mutants of HIV, but also multiply-mutant variants.