Antiretroviral therapy for patients with HIV disease

Barry, Michael; Mulcahy, Fiona; Back, David

doi:10.1046/j.1365-2125.1998.00673.x

Cited by 41 publications

(21 citation statements)

References 57 publications

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“…ADAM 9: IR (film) 3299.7, 3000.0, 2949. 6 3′,3′′-Dichloro-4′,4′′-dimethoxy-5′,5′′-bis(methoxycarbonyl)-1,1-diphenyl-1,6-heptadiene (10). TiCl4/THF 1:2 complex (0.7034 g, 2.1066 mmol) was added to a dry twonecked flask, under an argon atmosphere, equipped with a condensor, magnetic stir bar, and a rubber septum.…”

Section: 1-bis[3-bromo-4-methoxy-5-(methoxycarbonyl)phenyl]hept-1-ementioning

confidence: 99%

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

Micklatcher

Silvestri

et al. 2001

J. Med. Chem.

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In an effort to elucidate a set of structure-activity relationships in the alkenyldiarylmethane (ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications were made at two locations: (1) the meta positions of the two aromatic rings and (2) the end of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cell culture and for inhibition of HIV-1 reverse transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with optimal activity appearing with Cl, CH(3), and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF(3)) substituents. The substituents at the end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity associated with methyl or ethyl ester groups and with diminished activity resulting from substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals, ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar EC(50) values for inhibition of the cytopathic effect of HIV-1(RF) in CEM-SS cells. Selected ADAMs, 19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1 clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype representative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were more effective against the A98G mutation (found in association with nevirapine resistance in vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21 was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at preventing virus replication. Thus, we have identified a novel series of reverse transcriptase inhibitors with a favorable profile of antiviral activity against the primary mutation involved in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain activity against a multidrug-resistant virus.

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Section: 1-bis[3-bromo-4-methoxy-5-(methoxycarbonyl)phenyl]hept-1-ementioning

confidence: 99%

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

Micklatcher

Silvestri

et al. 2001

J. Med. Chem.

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“…[1][2][3][4] However the protease inhibitors have the secondary pharmacologic property of altering drug-metabolizing capacity, either through induction or inhibition of the activity or human cytochromes P450. 5,6 This property accounts for a number of pharmacokinetic drug interactions involving the protease inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Desipramine Hydroxylation (Cytochrome P450-2D6) in Vitro by Quinidine and by Viral Protease Inhibitors: Relation to Drug Interactions in Vivo

Moltke¹,

Greenblatt²,

Duan³

et al. 1998

Journal of Pharmaceutical Sciences

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Pharmacokinetic drug interactions with viral protease inhibitors are of potential clinical importance. An in vitro model was applied to the quantitative identification of possible interactions of protease inhibitors with substrates of cytochrome P450-2D6. Biotransformation of desipramine (DMI) to hydroxydesipramine (OH-DMI), an index reaction used to profile activity of human cytochrome P450-2D6, was studied in vitro using human liver microsomes. Quinidine and four viral protease inhibitors currently used to treat human immunodeficiency virus infection were tested as chemical inhibitors in this system. Formation of OH-DMI from DMI was consistent with Michaelis-Menten kinetics, having a mean Km value of 11.7 microM (range: 9.9-15.3 microM). Quinidine, a highly potent and relatively selective inhibitor of P450-2D6, strongly inhibited OH-DMI formation with an apparent competitive mechanism, having a mean inhibition constant of 0.16 microM (range: 0.13-0.18 microM). All four protease inhibitors impaired OH-DMI formation; the pattern was consistent with a mixed competitive-noncompetitive mechanism. Mean inhibition constants (small numbers indicating greater inhibiting potency) were as follows: ritonavir, 4.8 microM; indinavir, 15.6 microM; saquinavir, 24.0 microM; nelfinavir, 51.9 microM. In a clinical pharmacokinetic study, coadministration of ritonavir with DMI inhibited DMI clearance by an average of 59%. The in vitro findings, together with observed plasma ritonavir concentrations, provided a reasonable quantitative forecast of this interaction, whereas estimated unbound plasma or intrahepatic ritonavir concentrations yielded poor quantitative forecasts. Thus the in vitro model correctly identifies ritonavir as a potent and clinically important inhibitor of human P450-2D6. Other protease inhibitors may also inhibit 2D6 activity in humans, but with lower potency than ritonavir.

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“…Chemotherapy for HIV type-1 (HIV-1) has been significantly improved since the introduction of highly active antiretroviral therapy (HAART), containing two reverse transcriptase inhibitors and a protease inhibitor [1,2]. These drug regimens have been successful in producing sustained reductions in viral load and are associated with enhanced immune function and improved patient survival [3,4].…”

Section: Introductionmentioning

confidence: 99%

In Vivo and In Vitro Comparison of the Short‐Term Hematopoietic Toxicity Between Hydroxyurea and Trimidox or Didox, Novel Ribonucleotide Reductase Inhibitors with Potential Anti‐HIV‐1 Activity

et al. 1999

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Inhibitors of the cellular enzyme ribonucleotide reductase (hydroxyurea, [HU]) have been proposed as a new therapeutic strategy for the treatment of HIV type-1 (HIV-1) infection. However, HU use may be limited by the frequent development of hematopoietic toxicity. We report here short-term hematopoietic toxicity in mice receiving HU when compared to either of two more potent enzyme inhibitors, didox (DX) and trimidox (TX). High dose HU, DX, and TX monotherapy (500, 460, and 220 mg/kg/day respectively) was administered by daily i.p. injection (Monday-Friday) to C57BL/6 mice for 10 weeks. Effects on hematopoiesis were established by quantitating peripheral blood indices (hematocrit, hemoglobin, mean corpuscular volume, mean cell hemoglobin, mean corpuscular hemoglobin concentration, RBC, and WBC) and numbers of colony-forming units-granulocyte-macrophage (CFU-GM) and BFU-E from bone marrow and spleen. HU produced rapid induction of a macrocytic hypochromic anemia and altered white blood cell kinetics associated with myelosuppression defined as reduced marrow organ cellularity and induction of splenic extramedullary hematopoiesis. Compared to HU, TX and DX induced fewer changes in peripheral blood indices and CFU-GM and BFU-E per hematopoietic organ. In vitro human and murine marrow CFU-GM and BFU-E colony formations were assayed in the presence of dose escalation HU, DX, or TX (0, 1, 10, 50, 100, and 200 µM). HU inhibited colony formation more than either DX or TX. These in vivo and in vitro studies suggest that novel ribonucleotide reductase inhibitors TX and DX may provide an effective alternative to HU in HIV-1 therapy because they demonstrate reduced hematopoietic toxicity.

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Antiretroviral therapy for patients with HIV disease

Cited by 41 publications

References 57 publications

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

Inhibition of Desipramine Hydroxylation (Cytochrome P450-2D6) in Vitro by Quinidine and by Viral Protease Inhibitors: Relation to Drug Interactions in Vivo

In Vivo and In Vitro Comparison of the Short‐Term Hematopoietic Toxicity Between Hydroxyurea and Trimidox or Didox, Novel Ribonucleotide Reductase Inhibitors with Potential Anti‐HIV‐1 Activity

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