Phosphate moiety in FDA‐approved pharmaceutical salts and prodrugs

Fulmali, Ameya; Bharate, Sonali S.

doi:10.1002/ddr.21953

Cited by 14 publications

(7 citation statements)

References 73 publications

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“…This is not only advantageous for the uptake of nutrients from the environment and their conversion into phosphometabolites for feeding into the metabolism of healthy cells, but also for the design of pharmaceuticals as prodrugs and their mechanism of action in the treatment of diseased cells. The phosphate moiety has a long history of FDA-approved pharmaceuticals applied in a prodrug form, from hydrocortisone phosphate approved as first prodrug in 1952 to the 17 phosphate prodrugs approved until 2022 [ 54 ]. The phosphoramidate prodrug approach, which was named as ProTide approach, was developed by the McGuigan group and uses the masking of the monophosphate or monophosphonates of nucleoside analogues for efficiently delivering into cells where, after cleavage by intracellular enzymes, the bioactive free nucleoside monophosphates and monophosphonates are released [ 55 ].…”

Section: Structures Of Biologically Active Phosphometabolitesmentioning

confidence: 99%

Advances in the Synthesis and Analysis of Biologically Active Phosphometabolites

Wohlgemuth

2023

IJMS

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Phosphorus-containing metabolites cover a large molecular diversity and represent an important domain of small molecules which are highly relevant for life and represent essential interfaces between biology and chemistry, between the biological and abiotic world. The large but not unlimited amount of phosphate minerals on our planet is a key resource for living organisms on our planet, while the accumulation of phosphorus-containing waste is associated with negative effects on ecosystems. Therefore, resource-efficient and circular processes receive increasing attention from different perspectives, from local and regional levels to national and global levels. The molecular and sustainability aspects of a global phosphorus cycle have become of much interest for addressing the phosphorus biochemical flow as a high-risk planetary boundary. Knowledge of balancing the natural phosphorus cycle and the further elucidation of metabolic pathways involving phosphorus is crucial. This requires not only the development of effective new methods for practical discovery, identification, and high-information content analysis, but also for practical synthesis of phosphorus-containing metabolites, for example as standards, as substrates or products of enzymatic reactions, or for discovering novel biological functions. The purpose of this article is to review the advances which have been achieved in the synthesis and analysis of phosphorus-containing metabolites which are biologically active.

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Section: Structures Of Biologically Active Phosphometabolitesmentioning

confidence: 99%

Advances in the Synthesis and Analysis of Biologically Active Phosphometabolites

Wohlgemuth

2023

IJMS

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“…S.C. ALT-803 reduced the blood alkaline phosphatase (ALP) and creatinine levels but did not affect the aspartate, alanine aminotransferases, and blood urea nitrogen levels, suggesting that ALT-803 shows no hepatotoxicity and nephrotoxicity ( 21 , 22 ). Phosphate ester prodrugs (such as etoposide phosphate and fosamprenavir) are rapidly cleaved into the active compound by human ALP ( 26 ), suggesting that ALT-803 cannot be combined with phosphate ester prodrugs.…”

Section: The Preclinical Evidence Of Using Alt-803 In Nmibcmentioning

confidence: 99%

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential

et al. 2022

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Bladder cancer (BCa) is one of the most common malignant tumors that cause death. Approximately 75%–85% of BCa develop into non-muscle-invasive bladder cancer (NMIBC). Bacillus Calmette-Guérin (BCG) is the gold standard for avoiding cystectomy in the treatment of NMIBC. Unfortunately, up to 30% of patients do not respond to BCG treatment, and up to 70% of BCG responders relapse. The United States Food and Drug Administration (FDA) approved valrubicin (1998) and pembrolizumab (2020) for the treatment of BCG-unresponsive (BCGu) NMBIC. However, the complete remission rate for valrubicin and pembrolizumab was only 16% and 40.6%, respectively. ALT-803 (N-803) is an IL-15 superagonist and reduces tumor burden by promoting the proliferation and activation of NK cells and CD8+ T cells. The FDA received (23 May 2022) and accepted to review (28 July 2022) the marketing submission of ALT-803 plus BCG for the treatment of BCGu NMIBC. However, the FDA previously rejected the application for oportuzumab monatox (OM) due to a lack of data comparing it with pembrolizumab on August 20, 2021. Interestingly, the clinical efficacy and safety of ALT-803 were higher than that of pembrolizumab and OM, suggesting that ALT-803 may be approved by FDA. This review aims to further knowledge of the preclinical and clinical evidence of ALT-803 in the treatment of NMIBC and discuss its translational potential.

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“…Many phosphate ester prodrugs have also been approved by the FDA, suggesting that designing the phosphate ester prodrug of PF-00835231 could increase its aqueous solubility. PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into PF-00835231 by ALP, which then suppresses SARS-CoV-2 infection (Fulmali A, 2022).…”

Section: The Binding Sites Of Pf-00835231 and M Promentioning

confidence: 99%

Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection

et al. 2022

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Main protease (Mpro) is a superior target for anti-SARS-COV-2 drugs. PF-07304814 is a phosphate ester prodrug of PF-00835231 that is rapidly metabolized into the active metabolite PF-00835231 by alkaline phosphatase (ALP) and then suppresses SARS-CoV-2 replication by inhibiting Mpro. PF-07304814 increased the bioavailability of PF-00835231 by enhancing plasma protein binding (PPB). P-glycoprotein (P-gp) inhibitors and cytochrome P450 3A (CYP3A) inhibitors increased the efficacy of PF-00835231 by suppressing its efflux from target cells and metabolism, respectively. The life cycle of SARS-CoV-2 is approximately 4 h. The mechanisms and efficacy outcomes of PF-00835231 occur simultaneously. PF-00835231 can inhibit not only cell infection (such as Vero E6, 293T, Huh-7.5, HeLa+angiotensin-converting enzyme 2 (ACE2), A549+ACE2, and MRC-5) but also the human respiratory epithelial organ model and animal model infection. PF-07304814 exhibits a short terminal elimination half-life and is cleared primarily through renal elimination. There were no significant adverse effects of PF-07304814 administration in rats. Therefore, PF-07304814 exhibits good tolerability, pharmacology, pharmacodynamics, pharmacokinetics, and safety in preclinical trials. However, the Phase 1 data of PF-07304814 were not released. The Phase 2/3 trial of PF-07304814 was also suspended. Interestingly, the antiviral activities of PF-00835231 derivatives (compounds 5–22) are higher than, similar to, or slightly weaker than those of PF-00835231. In particular, compound 22 exhibited the highest potency and had good safety and stability. However, the low solubility of compound 22 limits its clinical application. Prodrugs, nanotechnology and salt form drugs may solve this problem. In this review, we focus on the preclinical data of PF-07304814 and its active metabolite derivatives to hopefully provide knowledge for researchers to study SARS-CoV-2 infection.

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Phosphate moiety in FDA‐approved pharmaceutical salts and prodrugs

Cited by 14 publications

References 73 publications

Advances in the Synthesis and Analysis of Biologically Active Phosphometabolites

Advances in the Synthesis and Analysis of Biologically Active Phosphometabolites

ALT-803 in the treatment of non-muscle-invasive bladder cancer: Preclinical and clinical evidence and translational potential

Review of preclinical data of PF-07304814 and its active metabolite derivatives against SARS-CoV-2 infection

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