Trends in oral small-molecule drug discovery and product development based on product launches before and after the Rule of Five

Stegemann, Sven; Moreton, Chris; Svanbäck, Sami; Box, Karl; Motte, G; Paudel, Amrit

doi:10.1016/j.drudis.2022.103344

Cited by 18 publications

(10 citation statements)

References 85 publications

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“…The importance of optimization in the beyond Ro5 space constituting macrocyclic and flexible molecules for oral drugs was recently reemphasized. , By the use of MicroED, we have determined the atomic structures of several macrocycles directly from nanograms of powder material without any prior crystallization, thereby giving access to previously unattainable structures. Despite their wide use, many of the macrocycles described herein were previously not described in the unbound state due to difficulties in growing the appropriate size crystals for XRD.…”

Section: Discussionmentioning

confidence: 99%

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

Danelius,

Bu,

Wieske

et al. 2023

ACS Chem. Biol.

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Macrocycles are important drug leads with many advantages including the ability to target flat and featureless binding sites as well as to act as molecular chameleons and thereby reach intracellular targets. However, due to their complex structures and inherent flexibility, macrocycles are difficult to study structurally, and there are limited structural data available. Herein, we use the cryo-EM method MicroED to determine the novel atomic structures of several macrocycles that have previously resisted structural determination. We show that structures of similar complexity can now be obtained rapidly from nanograms of material and that different conformations of flexible compounds can be derived from the same experiment. These results will have an impact on contemporary drug discovery as well as natural product exploration.

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Section: Discussionmentioning

confidence: 99%

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

Danelius,

Bu,

Wieske

et al. 2023

ACS Chem. Biol.

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“…[68] Our data would suggest that at least part of the false negative preclinical safety assessments could be attributed to excessive absorption of hydrophobic compounds in conventional in vitro toxicity assays. Thus, in light of the current drug development trends that favor increasing proportions of hydrophobic drugs over the last 25 years [69,70] and the resourceintensive process of lead compound modifications, selecting polymers with lower absorption across a wider logP range can be expected to improve the translatability of pharmacological and toxicological in vitro assessments.…”

Section: Discussionmentioning

confidence: 99%

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

Kemas,

Zandi Shafagh,

Taebnia

et al. 2023

Adv Healthcare Materials

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Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000‐fold between polymers with polydimethyl siloxane (PDMS) being most absorptive, whereas polytetrafluoroethylene (PTFE) and thiol‐ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations, whereas isogenic cultures in PDMS devices are resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability.

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“…Therefore, careful consideration should be given to the choice of dissolution media in terms of its composition, volume, and stirring rate during the in vitro assessment of OIDPs, especially due to the lack of standardized methods. Common APIs used in the formulation of orally inhaled products have a wide spectrum of solubility, with current trends in drug discovery moving towards high molecular weight and low solubility drugs [ 66 ]. Moreover, a relationship has been established between solubility, which is a thermodynamic property in nature, and dissolution rate, which is a kinetic property [ 17 , 67 ].…”

Section: Optimization Of Dissolution Medium For Orally Inhaled Drug P...mentioning

confidence: 99%

In Vitro Dissolution and Permeability Testing of Inhalation Products: Challenges and Advances

2023

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In vitro dissolution and permeability testing aid the simulation of the in vivo behavior of inhalation drug products. Although the regulatory bodies have specific guidelines for the dissolution of orally administered dosage forms (e.g., tablets and capsules), this is not the case for orally inhaled formulations, as there is no commonly accepted test for assessing their dissolution pattern. Up until a few years ago, there was no consensus that assessing the dissolution of orally inhaled drugs is a key factor in the assessment of orally inhaled products. With the advancement of research in the field of dissolution methods for orally inhaled products and a focus on systemic delivery of new, poorly water-soluble drugs at higher therapeutic doses, an evaluation of dissolution kinetics is proving crucial. Dissolution and permeability testing can determine the differences between the developed formulations and the innovator’s formulations and serve as a useful tool in correlating in vitro and in vivo studies. The current review highlights recent advances in the dissolution and permeability testing of inhalation products and their limitations, including recent cell-based technology. Although a few new dissolution and permeability testing methods have been established that have varying degrees of complexity, none have emerged as the standard method of choice. The review discusses the challenges of establishing methods that can closely simulate the in vivo absorption of drugs. It provides practical insights into method development for various dissolution testing scenarios and challenges with dose collection and particle deposition from inhalation devices for dissolution tests. Furthermore, dissolution kinetic models and statistical tests to compare the dissolution profiles of test and reference products are discussed.

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Trends in oral small-molecule drug discovery and product development based on product launches before and after the Rule of Five

Cited by 18 publications

References 85 publications

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

MicroED as a Powerful Tool for Structure Determination of Macrocyclic Drug Compounds Directly from Their Powder Formulations

Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

In Vitro Dissolution and Permeability Testing of Inhalation Products: Challenges and Advances

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