Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Wiemer, Andrew J.; Wiemer, David F.

doi:10.1007/128_2014_561

Cited by 146 publications

(136 citation statements)

References 225 publications

(239 reference statements)

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“…This can be attributed to the ability of hydrolases to act on the carbonate portion of the POC ester away from the benzoate carbonyl moiety. 15 This is in a good agreement with the enhanced plasma levels of 1 following oral administration of 30 as compared to 23 (Figure 2). …”

Section: Resultssupporting

confidence: 84%

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Rais¹,

Vávra

Tichý

et al. 2017

J. Med. Chem.

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4-Carboxy-α-[3-(hydroxyamino)-3-oxopropyl]-benzenepropanoic acid 1 is a potent hydroxamate-based inhibitor of glutamate carboxypeptidase II. In an attempt to improve its poor oral pharmacokinetics, we synthesized a series of prodrugs by masking its hydrophilic hydroxamate group. Prodrugs were evaluated for oral availability in mice and showed varying degree of plasma exposure to 1. Of these, para-acetoxybenzyl-based, 4-(5-(((4-acetoxybenzyl)oxy)amino)-2-carboxy-5-oxopentyl)benzoic acid, 12, provided 5-fold higher plasma levels of 1 compared to oral administration of 1 itself. Subsequently, para-acetoxybenzyl-based prodrugs with additional ester promoiety(ies) on carboxylate(s) were examined for their ability to deliver 1 to plasma. Isopropyloxycarbonyloxymethyl (POC) ester 30 was the only prodrug that achieved substantial plasma levels of 1. In vitro metabolite identification studies confirmed stability of the ethyl ester of benzoate while the POC group was rapidly hydrolyzed. At oral daily dose-equivalent of 3 mg/kg, 12 exhibited analgesic efficacy comparable to dose of 10 mg/kg of 1 in the rat chronic constrictive injury model of neuropathic pain.

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Section: Resultssupporting

confidence: 84%

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Rais¹,

Vávra

Tichý

et al. 2017

J. Med. Chem.

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show abstract

“…kinase bypass). 31 Our initial hypothesis in the current studies was that prodrug 4 would exhibit even stronger potency due to its ability to deliver a molecule that more closely mimics the natural ligand, which also contains two phosphorus groups rather than one. Indeed, prodrug 4 also imparts a strong fold increase in activity relative to the unprotected sodium salt 10 .…”

Section: Discussionmentioning

confidence: 99%

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

et al. 2017

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Butyrophilin 3A1 (BTN3A1) binds small phosphorous-containing molecules, which initiates transmembrane signaling and activates butyrophilin-responsive cells. We synthesized several phosphinophosphonates and their corresponding tris-pivaloyloxymethyl prodrugs and examined their effects on BTN3A1. An analog of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) bound to BTN3A1 with intermediate affinity, which was enthalpy-driven. Docking studies revealed binding to the basic surface pocket and interactions between the allylic hydroxyl group and the BTN3A1 backbone. The phosphinophosphonate stimulated proliferation of Vγ9Vδ2 T cells with moderate activity (EC50 = 26 µM). Cellular potency was enhanced >600-fold in the tris-POM prodrug (EC50 = 0.041 µM). The novel prodrug also induced T cell mediated leukemia cell lysis. Analysis of dose response data reveals HMBPP-induced Hill coefficients of 0.69 for target cell lysis and 0.68 in interferon secretion. Together, tris-POM prodrugs enhance the cellular activity of phosphinophosphonates, reveal structure-activity relationships of butyrophilin ligands, and support a negatively cooperative model of cellular butyrophilin activation.

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“…8 For example, the pivaloyloxymethyl (POM) derivative 9 is much more hydrophobic in terms of a calculated ClogP and also demonstrates cellular activity at lower concentrations. 10 More recently, we have prepared some triazole bisphosphonates through click chemistry 11 of an acetylene bisphosphonate 12 and various isoprenoid azides.…”

mentioning

confidence: 99%

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

Wills

Allen

Holstein

et al. 2015

ACS Med. Chem. Lett.

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Studies of triazole bisphosphonates have resulted in identification of a potent inhibitor of geranylgeranyl diphosphate synthase (IC 50 = 45 nM) with very good selectivity for this enzyme over farnesyl diphosphate synthase (IC 50 = 28 μM). This compound also potently disrupts geranylgeranylation and induces cytotoxicity in human myeloma cells at submicromolar levels, suggesting that it may serve as a lead compound for treatment of malignancies characterized by excessive protein secretion.

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Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

Cited by 146 publications

References 225 publications

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Phosphinophosphonates and Their Tris-pivaloyloxymethyl Prodrugs Reveal a Negatively Cooperative Butyrophilin Activation Mechanism

Potent Triazole Bisphosphonate Inhibitor of Geranylgeranyl Diphosphate Synthase

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