Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery

Wuelfing, W. Peter; Marrouni, Abdellatif El; Lipert, Maya P.; Daublain, Pierre; Kesisoglou, Filippos; Converso, Antonella; Templeton, Allen C.

doi:10.1021/acs.jmedchem.1c01687

Cited by 11 publications

(6 citation statements)

References 56 publications

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“…In formulation studies, the compound was found to have excellent solubility (4.5 mg/mL, Table ) and a dose number of less than 1. In combination with the projected human dose, these data suggest that MK-7845 is suitable for oral BID administration using conventional formulation …”

Section: Results and Discussionmentioning

confidence: 91%

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

Shurtleff,

Layton,

Parish

et al. 2024

J. Med. Chem.

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As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

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Section: Results and Discussionmentioning

confidence: 91%

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

Shurtleff,

Layton,

Parish

et al. 2024

J. Med. Chem.

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“…Assessment of challenges in oral delivery of the exceedingly water-insoluble drugs, such as dasabuvir, is often based on the dose number which takes into consideration of both solubility and dose. ,, The dose number is equal to dose divided by solubility and human GI volume. With the estimated human dose of 400 mg and the intrinsic aqueous solubility of 0.122 μg/mL, the calculated dose number for dasabuvir is 1.31 × 10 4 .…”

Section: Results and Discussionmentioning

confidence: 99%

“…The calculated dose number of dasabuvir is 1.31 × 10 4 based on its solubility and dose. As dose numbers higher than 10 are associated with risks of solubility-limited absorption, 8 dasabuvir's incredibly high dose number underlines a significant challenge for its oral delivery. The measured Caco-2 permeability for this drug is approximately 40 × 10 −6 cm/s, indicating that it is highly permeable.…”

Section: Introductionmentioning

confidence: 99%

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery

et al. 2022

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Dasabuvir is a non-nucleoside polymerase inhibitor for the treatment of hepatitis C virus (HCV) infection. It is an extremely weak diacidic drug (pK a = 8.2 and 9.2) and a prolific solvate former. Due to its exceedingly low aqueous solubility (≤0.127 μg/mL at pH 1−6.8, dose number of 1.31 × 10 4 ), crystalline dasabuvir free acid exhibited poor oral bioavailability in initial animal pharmacokinetic (PK) assessment. This necessitated the development of enabling formulation for human clinical studies to achieve the required therapeutic in vivo concentration of dasabuvir. While salt formation has been widely used to enhance the solubility and dissolution rate of solids, this approach has rarely been applied to develop oral solid dosage forms for acidic drugs as weak as dasabuvir due to concerns of rapid disproportionation and crystallization of its free acid. In this contribution, we detail our efforts in identifying dasabuvir monosodium monohydrate as a drug substance that is stable, manufacturable, and, most importantly, significantly enhances the dissolution and oral absorption of this poorly soluble drug. The oral delivery of dasabuvir through the salt approach has enabled the commercialization of the triple-combination direct-acting antiviral HCV regimen, Viekira Pak. The methodologies and solutions identified in targeted studies to overcome technical challenges encountered along the way (i.e., incorporation of polymers to inhibit crystallization and disproportionation and species mapping to enable salt manufacturing process, etc.) can be applied to other insoluble compounds.

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“…In this context, the Dose number (Do) is a functional parameter to simply describe the ratio of available solid drug to the thermodynamically soluble amount in a certain amount of dissolution media. Do was introduced by Amidon et al in the 1990s [73,74] and the parameter has become a standard to assess and classify the risk for oral absorption in terms of dissolution [75][76][77][78][79][80].…”

Section: Modeling Methodsmentioning

confidence: 99%

Numerical modelling of the dissolution of drug nanocrystals and its application to industrial product development

et al. 2022

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The apparent solubility of drug nanocrystals in equilibrium was experimentally determined for a drug-stabilizer system with different particle size distributions. True supersaturation was identified for ultrafine drug nanocrystals with an almost 2-fold increase compared to the thermodynamic solubility of related coarse drug crystals, highlighting their enabling potential to enhance bioavailability. The experimental results were applied to investigate in silico the associated dissolution behavior in a closed system by numerical modeling according to the Ostwald-Freundlich and Noyes-Whitney / Nernst-Brunner equations. Calculated results were found to be in agreement with the experimental results only when the entire particle size distribution of drug nanocrystals was considered. In silico dissolution, studies were conducted to simulate the complex interplay between drug nanocrystals, dissolution conditions and resulting temporal progression during dissolution up to the equilibrium state. Calculations were performed for selected in vivo and in vitro scenarios considering different drug nanocrystal particle size distributions, drug amount, dissolution media and volume. The achieved results demonstrated the importance of ultrafine drug nanocrystals for potential bioavailability improvement and the functional applicability of the modeling approach to investigate their dissolution behavior for configurable formulation variables in product development in terms of in vivo and in vitro relevant conditions. ©2022 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).

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Dose Number as a Tool to Guide Lead Optimization for Orally Bioavailable Compounds in Drug Discovery

Cited by 11 publications

References 56 publications

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic

Overcoming Bioavailability Challenges of Dasabuvir and Enabling a Triple-Combination Direct-Acting Antiviral HCV Regimen through a Salt of Very Weak Acid for Oral Delivery

Numerical modelling of the dissolution of drug nanocrystals and its application to industrial product development

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