Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization

Nofsinger, Rebecca; Clas, S.‐D.; Sánchez, Rosa I.; Walji, Abbas M.; Manser, Kimberly; Nissley, Becky; Balsells, Jaume; Nair, A. M; Dang, Qun; Bennett, David Jonathan; Hafey, Michael; Wang, Junying; Higgins, John; Templeton, Allen C.; Coleman, Paul J.; Grobler, Jay A.; Smith, Ronald L.; Wu, Yunhui

doi:10.3390/ph7020207

Cited by 12 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next turned our focus toward the phenolic hydroxyl group (b) of the requisite bidentate metal binding pharmacophore inherent to all HIV InSTis, including compounds 7 and 8 . Based on our previous experience with prodrugs of RAL, , we suspected that the acidity and the ionizability of this hydroxyl group was likely impacting the permeability of the parent compounds. Therefore, we devised a similar strategy utilizing the acetal carbonate functionality as a permeability-enhancing promoiety.…”

Section: Resultsmentioning

confidence: 99%

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Raheem¹,

Walji²,

Klein³

et al. 2015

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.

show abstract

Section: Resultsmentioning

confidence: 99%

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Raheem¹,

Walji²,

Klein³

et al. 2015

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Earlier we presented an analysis of the impact of in vitro solubility and permeability on in vivo dog colonic absorption for a series of prodrugs, and lack of correlation between these data. [34] We recognized the difficulty in using in vitro tools to predict the extent of dog colonic absorption within this class of prodrug, and the challenge this presents for the design of prodrugs with a significant improvement (> 40 %) of dog colonic absorption. Additionally, the differences in physiology between the dog and human colonic environments (colonic pH; transit times) introduce further challenges in directly translating data from the dog model to the clinic.…”

Section: Resultsmentioning

confidence: 99%

“…However, they were all limited by a lack of correlation between increased lipophilicity compared with RAL ( Table 2) and relative colonic bioavailability. [34] To evaluate the extent to which an effective increase in lipophilicity was tolerated, the bis-isopropyl analogue 9 was further profiled. Although an improvement was measureable in vitro with 9, a significantly lower level of relative colonic bioavailability (10 %) was observed.…”

Section: Resultsmentioning

confidence: 99%

Discovery of MK‐8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption

Walji¹,

Sánchez

Clas³

et al. 2014

ChemMedChem

Self Cite

View full text Add to dashboard Cite

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.

show abstract

“…Prodrugs, by design, are developed to improve gut absorption and subsequent delivery to their targets. 26 In both drug designs, it is likely that their metabolism in the gut would reduce their efficacy due to the bacteria engaging in various enzymatic activities that directly reduce the drugs' likelihood of action or absorption, respectively.…”

Section: Commonly Prescribed Antihypertensive Medications Their Metab...mentioning

confidence: 99%

Resistance to Antihypertensive Drugs: Is Gut Microbiota the Missing Link?

2022

View full text Add to dashboard Cite

Microbiota colonization begins at birth and continuously reshapes throughout the course of our lives, resulting in tremendous interindividual heterogeneity. Given that the gut microbiome, similar to the liver, houses many categories of catalytic enzymes, there is significant value in understanding drug-bacteria interactions. The discovery of this link could enhance the therapeutic value of drugs that would otherwise have a limited or perhaps detrimental effect on patients. Resistant hypertension is one such subset of the hypertensive population that poorly responds to antihypertensive medications, resulting in an increased risk for chronic cardiovascular illnesses and its debilitating effects that ultimately have a detrimental impact on patient quality of life. We recently demonstrated that the gut microbiota is involved in the metabolism of antihypertensive drugs and thus contributes to the pathophysiology of resistant hypertension. Due to a lack of knowledge of the mechanisms, novel therapeutic approaches that account for the gut microbiota may allow for better therapeutic outcomes in resistant hypertension. Therefore, the purpose of this review is to summarize our current, albeit limited, understanding of how the gut microbiota may possess particular enzymatic activities that influence the efficacy of antihypertensive drugs.

show abstract

Design of Prodrugs to Enhance Colonic Absorption by Increasing Lipophilicity and Blocking Ionization

Cited by 12 publications

References 22 publications

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors

Discovery of MK‐8970: An Acetal Carbonate Prodrug of Raltegravir with Enhanced Colonic Absorption

Resistance to Antihypertensive Drugs: Is Gut Microbiota the Missing Link?

Contact Info

Product

Resources

About