Discovery and Development of HIV‐1 Entry Inhibitors That Target gp120

Kadow, John F.; Bender, John A.; Regueiro‐Ren, Alicia; Ueda, Yasutsugu; Wang, Tao; Yeung, Kap‐Sun; Meanwell, Nicholas A.

doi:10.1002/9780470929353.ch11

Cited by 3 publications

(4 citation statements)

References 37 publications

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“…Recently, a novel class of HIV-1 attachment inhibitors have been described that prevent the initial interaction between virus and host cell by binding to the gp120 protein on the viral envelope and thus interfere with the attachment of the virus to the CD4 receptor on CD4+ T-cells [ 3 ]. As is the case with many recently developed agents for the treatment of HIV infection [ 4 ] the therapeutic utility of these agents was challenged by their poor solubility and pharmacokinetic properties, requiring enabling approaches to be employed to allow the investigation of these agents in the clinic [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet

et al. 2022

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The uptake of alkaline phosphate present in dissolution medium into a hydrating hydroxypropyl methylcellulose matrix tablet and that its activity was retained therein was demonstrated. This presents a risk to the stability of prodrugs that are substrates of this enzyme such as phosphonooxymethyl derivative prodrugs. It was found that fostemsavir, a phosphonooxymethyl derivative prodrug being developed for the treatment of HIV-1 infection, was unexpectedly resistant to hydrolysis within a hydrated HPMC matrix when subjected to drug release testing in media containing alkaline phosphatase. Studies indicated that this was not due to microenvironmental pH effects, osmolality effects or effective phosphate concentration effects associated with the presence of the prodrug. That the prodrug and not its parent could affect enzyme activity in a concentration dependent manner, and that another phosphate ester prodrug fosphenytoin did not inhibit alkaline phosphatase activity within a hydrated HPMC matrix suggested that the unexpected stability of the HIV-1 therapy prodrug may be associated with the ability of the phosphate group-containing compound itself to inhibit the enzyme at the concentrations it exists at in the hydrated dosage form and so enables the development of the compound in this type of dosage form.

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Section: Introductionmentioning

confidence: 99%

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet

et al. 2022

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“…Small proteins mimicking CD4 þ have shown high potency against HIV-1 in-vitro [1] and in animal studies [2]. An alternative to inhibit effective gp120-CD4 þ binding is for a drug to bind to gp120 and block the conformational change in gp120 induced by CD4 þ [3][4][5]. The only drug with this mechanism of action currently approved for treatment is Fortemsavir and therefore this class of drugs provide an excellent option for prevention strategies to avoid transmission of resistant isolates.…”

Section: Introductionmentioning

confidence: 99%

The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate

Herrera

Harman

Aldon

et al. 2021

Aids

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Objective: Small molecule inhibitors able to bind to gp120 and prevent CD4 þ -induced HIV-1 envelope conformational change provide an important class of inhibitors. Currently, only Fostemsavir is approved for HAART, which makes this class of inhibitors attractive candidates for prevention. We assessed the activity of DS003 (BMS-599793), an analogue of BMS-378806, in different mucosal tissues and elucidated its mechanism of action.Design: Preclinical analysis was performed with human mucosal tissue models as surrogates of in-vivo activity.Methods: Antiviral efficacy of DS003 was assessed in mucosal tissue explants (ectocervical, penile and colorectal) and in trans-infection models (co-cultures of dendritic or mucosal migratory cells with CD4 þ T cells) with several dosing times (2, 24 h and sustained) and in combination with a fusion inhibitor. Binding of DS003 to gp120 was assessed by flow cytometry and bio-layer interferometry and further probed in competitive studies using soluble CD4 þ (sCD4 þ ) and an anti-CD4 þ induced antibody, 17b.Results: In all models, the inhibitory activity of DS003 was increased with longer periods of exposure and by combination with a fusion inhibitor. Pre-exposure to sCD4 þ impeded DS003 binding to viral envelope. In contrast, DS003 did not impact subsequent binding of sCD4 þ . Furthermore, sCD4 þ -induced epitope exposure as assessed by 17b binding was significantly reduced in the presence of DS003.Conclusion: DS003 inhibits HIV-1 infection by binding to or near the CD4 þ binding site of gp120, preventing CD4 þ -induced conformational change essential for viral fusion. These data highlight the potential of DS003 for development as a pre-exposure prophylaxis candidate.

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“…It was anticipated that this moiety would provide parent drug via the intermediacy of a short-lived hydroxymethyl intermediate 3 after phosphatase cleavage of prodrug 4 (BMS-663749) 34 and would offer considerable potential to provide a functional solution to the formulation problem (Scheme 1). 28,33,35,36 The purpose of this work was to prepare prodrug 4 and assess its potential to remedy the high dose and solubility limited absorption that were two significant reasons parent 2 was not a viable HIV-1 attachment inhibitor for use in combination therapy to treat HIV-1 infection.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Phosphate prodrugs, either directly attached to a molecule or incorporated via linkers, have been used to successfully enhance the solubility and exposure of a range of compounds administered by either an intravenous (IV) or oral route. − The physicochemical properties predictive of success with an oral phosphate prodrug approach have been studied, but due to the number of variables, the potential for utility must be assessed experimentally. , Previous experience with phosphate-based prodrugs of the antifungal agent ravuconazole and taxane derivatives suggested that a phosphonooxymethyl prodrug moiety might be readily attached to the indole nitrogen of 2 . It was anticipated that this moiety would provide parent drug via the intermediacy of a short-lived hydroxymethyl intermediate 3 after phosphatase cleavage of prodrug 4 (BMS-663749) and would offer considerable potential to provide a functional solution to the formulation problem (Scheme ). ,,, The purpose of this work was to prepare prodrug 4 and assess its potential to remedy the high dose and solubility limited absorption that were two significant reasons parent 2 was not a viable HIV-1 attachment inhibitor for use in combination therapy to treat HIV-1 infection.…”

Section: Introductionmentioning

confidence: 99%

Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment 6. Preclinical and Human Pharmacokinetic Profiling of BMS-663749, a Phosphonooxymethyl Prodrug of the HIV-1 Attachment Inhibitor 2-(4-Benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043)

et al. 2012

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BMS-663749, a phosphonooxymethyl prodrug 4 of the HIV-1 attachment inhibitor 2-(4-benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043) (2) was prepared and profiled in a variety of preclinical in vitro and in vivo models designed to assess its ability to deliver parent drug following oral administration. The data showed that prodrug 4 had excellent potential to significantly reduce dissolution rate-limited absorption following oral dosing in humans. Clinical studies in normal healthy subjects confirmed the potential of 4, revealing that the prodrug significantly increased both the AUC and C(max) of 2 compared to a solid capsule formulation containing the parent drug upon dose escalation. These data provided guidance for further efforts to obtain an effective HIV-1 attachment inhibitor.

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Discovery and Development of HIV‐1 Entry Inhibitors That Target gp120

Cited by 3 publications

References 37 publications

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet

Unexpected Stability of a Prodrug to Enzymatic Hydrolysis within a Hydrated HPMC Matrix Tablet

The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate

Inhibitors of Human Immunodeficiency Virus Type 1 (HIV-1) Attachment 6. Preclinical and Human Pharmacokinetic Profiling of BMS-663749, a Phosphonooxymethyl Prodrug of the HIV-1 Attachment Inhibitor 2-(4-Benzoyl-1-piperazinyl)-1-(4,7-dimethoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoethanone (BMS-488043)

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