Structural Characteristics of Listed Drugs: Analysis of the Development Trend of Small Molecule Drug Properties from "Developability Assessment" (Part I)

1

summary

As drug discovery strategies have advanced, the property-related failure rate of drug candidates during development has been significantly reduced from 39% in 1991 to 2 10% in 000, but drug toxicity, dosage form and other factors are still the key factors affecting the success rate of new drug development, and the improvement of drug toxicity and dosage form is still facing great challenges ^1]
。

At present, molecular developability evaluation is at the core of early drug discovery in the pharmaceutical industry, and the evaluation of the drug-like properties of compounds, such as solubility, permeability and stability, can effectively reduce the cost
of new drug development.
In the drug development stage, avoid increasing development time, economic costs and risks
due to poor molecular physical and chemical properties.

In addition, many property analyses of marketed drugs are mostly written from the perspective of drug discovery scientists, analyzing the structural properties of compounds to obtain drug-like molecules with better ADMET properties, but failing to analyze the impact
of drug structural properties on CMC development.

In order to systematically reveal the influence of the structural properties of drugs on the physical and chemical properties of drugs (such as solubility and permeability), Amgen selected a number of experts from the process development department Oral drugs approved by the FDA from 1900 to 2020 are analyzed in detail
.
The work was published in the journal Drug Discovery Today on September 17, 2022 ^2]
。

2

Preface

Developability molecule assessment (DevMA) or early candidate assessment ECA) is a key part of the drug discovery stage, estimating the physicochemical and biochemical characteristics of drug candidates, selecting appropriate dosage forms, ensuring drug stability, and making it suitable for clinical research
.
D evMA can be used as a risk assessment to fully and thoroughly evaluate lead molecules before and even at an earlier stage when R&D projects advance through costly clinical development, meeting the stability, dosage form, and manufacturability (QC-compliant scale-up) requirements of CMC development and reducing risk
。 If the physical and chemical properties of the molecule do not meet the needs of drug development, the molecular properties can be further optimized in the early stage of drug discovery to reduce the difficulty
of CMC development.

Highly lipophilic compounds are often considered suboptimal drug candidates because they affect the solubility, toxicity, efficacy, and manufacturability of the compound, resulting in high clinical development failure rates
.
For highly lipophilic, high-molecular-weight compounds that require CMC development, it is necessary to select appropriate dosage forms (e.
g.
, amorphous solid dispersions, liposome formulations) to successfully deliver
them orally by oral route.
In particular, selecting the right dosage form for an innovative drug is an important investment, but it does not mitigate off-target toxicity and heterogeneity of compounds
.

In order to reduce the attrition rate of new drug development (new drug development loss is different from clinical failure rate), loss is a broader term, including failure due to technical reasons, setbacks due to regulatory registration reasons, and project suspension due to business and corporate strategic reasons, although the reasons are different, the consequence is that the project does not continue to develop ^[3]), there are many drug screening guidelines widely used, most of which are summarized based on the structural properties of the compound (such as molecular weight, partition coefficient, ionization state, polarity, etc.
), which are used to optimize molecule A DMET properties, such as Lipinski's rule of 5, 3/75 rule, a bioavailability score, Veber's rule, etc
.
Based on these guidelines, it is currently found that most of the drugs approved for marketing are in a unique property space, and molecules that deviate from this space lead to additional economic burden and R&D risks
.
However, there are not many guidelines
for optimizing molecules based on CMC development considerations.

This review mainly analyzes the compounds in the Drug Repurposing Hub database from the perspective of De MA, and discusses the structural properties of compounds on CMC The development focuses on the influence of physicochemical properties and is divided into the following three aspects:

（1) Physicochemical properties vs drug approval year； To evaluate FDA-approved oral drugs and their molecular properties over
time.

（2) Physicochemical properties vs Phase of development； Important molecular properties that affect the loss rate of new drug development in the pharmaceutical industry and compare
them with Amgen molecules.

（3) Physicochemical properties vs drug target class and/or subclass； Explore the association between different physicochemical properties of drugs and protein target types, similar to target-based drug discovery

This article mainly introduces the first part, Physicochemical properties vs drug approval year, and introduces the changes in the structural properties of FDA-approved drugs over time and solubility, permeability, and ADMET and the impact of manufacturability
。 The second and third parts will be introduced
in the next issue.

3

Data management and quantitative metrics

The Drug Repurposing Hub database is a comprehensive database of small molecule compounds, annotating
information on molecular research progress, targets, indications, and mechanisms of action.
The database was first launched in 2017 and updated in April 2020, with a total of 7 collections 000 molecules, including 9 64 orally administered molecules approved by the FDA (as of 2020)
。

In this review, the authors reclassified
lipophilicity.
The lipophilicity of a molecule is defined by polar surface area (PSA) and polarity and hydrogen bonds in the partition coefficient (cLogP), which can be used to identify molecules
that have successfully penetrated the biofilm.
PSA is related to molecular weight (Molecular weight, Mw), in order to eliminate the effect of Mw, The authors defined valid PSA (%PSA/Mw, effective PSA, ePSA ), similar data preprocessing has been used to predict
the excretion and clearance of drugs.
The lipophilicity of compounds is divided into four categories based on cLogP and ePSA: very high (cLog P > 3 and ePSA < 20 %) ; high(cLogP > 3 and ePSA > 20 %); moderate(cLogP < 3 and ePSA < 20%); and low(cLogP < 3 and ePSA > 20%)
.
All structural properties mentioned in this article are based on the ACD Percepta platform (2017.
2.
1) forecasts
.

4

Physicochemical properties vs drug approval year 

Many experts believe that among the many structural properties of marketed drugs, it is the most important property
of drugs that do not change over time.
An analysis of FDA-approved oral drugs found that MW increased with approval time (as shown in Figure 1).

The impact of MW on drug development needs to be carefully considered, and complex compounds with high molecular weight will not only cause resource burden, but also affect the subsequent molecular optimization process
.
In addition, the impact on oral bioavailability needs to be carefully considered, but with the recent approval of semaglutide oral drugs, human oral absorption drugs are no longer limited by the specific value of molecular size, and the selection of reasonable formulations and dosage forms can enhance the oral bioavailability of drugs (adding oral osmotic enhancers).

Figure 1.
Schematic diagram of the physical and chemical properties of FDA-approved drug molecules over time

Similar to the growing trend of Mw, in the structural properties of drugs, PSA, rotatable bonds (RB).
H-bond acceptors (HBAs) are also on the rise
.
c LogP, c LogD_{pH 6.
5}, at 2 Drugs approved for marketing before 010 remained stable, but increased by about 1 log from 2011 to 2020 (Figure 1）
。 In the lipophilic quadrant plots defined by c LogP and ePSA, high and very high The share of categories rose to 54% between 2011 and 2020 (see Figure 2a for details).

The only thing that hasn't changed significantly is the number of H-bond donors (HBD) of the drug, and one of the reasons it has remained the same is HBD The effect on molecular permeability and melting point has been studied
in detail.
In addition, the drug similarity parameter sp3 fraction of sp3 carbons (Fsp3) has decreased to 0.
37 in the past decade , may be related to the launch of more kinase-targeting drugs in the past decade (Figure 2C), and drugs targeting kinases mostly have purine ring-like structures
.

Figure 2 Statistics on the trend of changes in the properties of oral drugs approved by the FDA in different time periods (a) lipophilicity; (b) ion type; (c) Target category

The authors further analyzed oral drugs based on Mw and cLog P grouped by year of approval (as shown in Figure 3), and found in particular at 2 From 011 to 2020, there was a significant change in the values of Mw and c LogP, with each increase of Mw by 1 00Da, cLogP adds 1.
5 logs
。 One possible explanation for this is the development of larger and more complex skeletons (e.
g.
, macrocyclic drugs)
due to technological advances in genetics, combinatorial chemistry, high-throughput screening, and increasing interest in undruggable targets in the pharmaceutical industry.

Figure 3 Changes in cLogP and Mw of FDA-approved oral drugs in different time periods

5

Solubility, permeability, ADMET and manufacturability

To facilitate the discussion of the influence of the structural properties of molecules on the development of drug CMCs, the authors discuss in detail the effects
of structural properties of drugs on solubility, permeability, ADMET, and manufacturability.

Solubility

The low solubility of the compound leads to low absorption of the compound, low bioavailability after oral administration, and the need for high doses; In addition, insufficient solubility also makes it impossible to administer high-dose drugs intravenously, resulting in increased formulation development costs and extended R&D time in CMC ^{development [1].}

The general solubility equation proved by Yalkowsky relies mainly on two parameters: logP and melting point (Tm, °C), and the solubility difference of the compound may be hydrophobicity (solvation limited solubility/hydrophobicity: Kow), solid-state-limited solubility/lattice energy: TM) related
.
In oral molecules approved for marketing in 2011-2020, the parameters in the general dissolution equation [Kow (▲cLogP) and Tm (▼ Fsp3 and HBA)] both increased (Fsp3 decreased, solubility decreased), indicating that the solubility of approved molecules in the past decade is decreasing
。 In addition, recent studies have shown that increases in HBD and HBA contribute to crystal accumulation, leading to higher melting points (although increases in HBA and HBD increase increase water solubility, but are offset by a larger lattice
。 In addition to this, Stutherland et al.
analyzed in the review that Mw increase had little effect
on solubility.

At present, in the development of CMC, the common formulations to solve the poor water solubility are amorphous solid dispersions and liposome formulations, and the number of related commercial products is steadily increasing
.

permeability

Permeability/permeability is a measure of the rate at which a compound passes through the structure of the lipid membrane, and permeability also affects the internal processes of the drug, such as oral intestinal absorption, distribution, metabolism and excretion, which in turn affects the efficacy of the drug ^[1]
。

The polarity of molecules is very important for predicting the permeability of molecules, and molecules with higher polarity tend to have lower
permeability.
At present, the use of PSA to predict the permeability of small molecules has achieved some success, but the advantages and disadvantages of this prediction have also been paid attention
to by researchers.
In addition, there has been a recent general focus on 3D PSAs for high molecular weight and macrocyclic drugs, larger molecules with chameleon-related properties that undergo conformational transformation as they cross the lipid membrane: polar groups are exposed in aqueous solution, while polar groups are masked by intramolecular hydrogen bonds when permeabilizing
.
Whitty et al.
analyzed that when the compound Mw > 700 Da, it is necessary to ensure that PSA> 0.
2 Å is required to obtain molecules with better water solubility ²/Da x Mw, while good cell permeability requires guaranteed 3D PSA, the study has conflicting conclusions, but indirectly proves PSA , Mw is not directly related
to solubility.
Ross i et al.
found that when MW exceeds 500-700 Da, PSA is hidden in
the minimal energy conformation.
It was demonstrated that conformation-dependent PSA allowed these macromolecular drugs to adapt to their environment
in a chameleon-like fashion.
For molecules with Mw < 500 Da, accurate predictions
can be made based on criteria such as Lipinski's rules.

About 2,69of the7,196 compounds in the Drugrepurposing hub database molecules (~4%) tPSA > 140 Å and Mw > 700 Da, of which 38 are approved by the FDA for marketing
.
Now entering the fourth wave of new drug research and development, as well as the attention to high-molecular-weight drugs such as PROTAC and molecular glue, the transport characteristics of these macromolecules are expected to usher in a research boom
.

The above focuses on the effect of PSA on molecular permeability, the structural properties of other molecules, such as RB, LogP, HBA, HBD also affects the permeability
of drugs.
(1) In the FDA-approved oral drugs, the number of RB is increasing year by year, and the increase in molecular flexibility can improve solubility, but limit oral availability (which may be related to excessive conformational states of the compound and are not conducive to binding to the target).

(2) LogP increases with the increase of cell permeability, although cLogP is the gold standard for lipophilic calculation, it cannot explain the effect of ionization and hydrogen bonding on partitioning.
Only the partition of the compound in the neutral state can be predicted, and the pH-dependent log D calculation
is used for non-neutral molecules.
Waring et al.
analyzed > 9,000 compounds and found that log D Interdependent with Mw, the molecule Mw < 414 g/mol, log D> 1.
3 The molecule has high permeability; The Mw> 414 g/mol, log D> 2.
4 molecules have high permeability
.
(3) HBD and HBA numbers are important molecular descriptors that affect drug discovery and CMC development, and are among the oral molecules approved for marketing by the FDA HBA increased over time, but HBD did not change significantly (Figure 1).

Although the number of Mw, PSA, and RBs in marketed drugs increased, HBD did not change
with increasing molecular complexity.
HBD is an important factor influencing the passive transport of molecules, and the detection of solute–water H-bond energies showed that the energy from HBD-water was higher than that of HBA -water, therefore, HBD requires more energy
when permeable to the membrane than HBA.

In addition to this, analysis of Amgen compounds showed that the HBD and tPSA of the compounds < 90 Å2 Has the greatest chance of escaping P-gp efflux
.
At the same time, Lilly researchers pointed out that too many hydrogen bonds can lead to a decrease
in permeability.
However, the removal of HBD and HBA-associated groups from molecules may have a serious impact on the potency of the compound, so masking HBD and HBA through intermolecular and intramolecular hydrogen bonds may be a possible strategy to improve permeability
。

ADMET

ADMET is involved in the absorption, distribution, metabolism, excretion and toxicity
of drugs.
Oral absorption of drugs involves the dissolution of the drug in the gastrointestinal tract and the penetration of the cells of the intestinal wall, these processes are affected by the solubility and permeability of the drug, and these physicochemical properties are affected
by the various structural properties of the compound.
There have been many literature summarizing the criteria for optimizing the properties of molecular ADMET, and the most commonly used is Lipinski'srules of 5, which was later proposed by Veber et al RB and PSA<140 Å2 as considerations for enhanced oral bioavailability
.

In addition to this, the ionization (pKa) of the drug affects not only the ADMET properties of the drug and protein-ligand interactions, but also the oral bioavailability of the drug, according to Ma The rtin team proposed ABS (a bioavailability score) to determine the oral availability of a compound
.
The authors further suggest that PSA properties are important for oral availability of negatively charged acidic drugs, while other ionic types can be predicted
based on Lipinski's rules.
Among the oral molecules approved by the FDA, the percentage of various ionized drug types did not change significantly with the year of approval (Figure 2b), with anions accounting for 20%.

。

Increasing the affinity of molecules is often recommended as a way to compensate for ADMET deficiencies, however, Leeson et al.
noted in a review that the affinity of molecules / The increase in potency does not compensate for the defect that Mw, cLogP increases and ADMET properties are poor, and molecular affinity/potency can be passed through Mw OR cLogP for correction
.
The authors further suggest that in target-based drug discovery, the ligand efficiency (LE) and lipophilic ligand potency (lipophilic ligand) of the drug candidate are available efficiency, LIE) should be greater than the median value
of the target-related ligand.

Manufacturability

Manufacturability is defined in this review as large-scale, high-quality production
in accordance with safety and efficacy requirements while controlling costs.
Physical properties such as complexity, stability, and solubility of the drug structure can affect manufacturability
.

(1) Compounds with a lower number of RB have a lower number of potential conformations, and it is easier to obtain crystallization and precipitation
quickly.
In FDA-approved oral molecules, the amount of RB increased significantly over time (Figure 1).

The conformation of newly approved drug molecules has increased, and the industry may need more comprehensive crystal form screening
.

(2) In addition, the ratio of HBA to HBD is related
to the formation of hydrates and solventates.
This value is increasing in FDA-approved drugs, indicating an increased
likelihood of solventate formation.
The theoretical basis comes from the analysis of the Cambridge structural database: the imbalance of the proportion of hydrogen bond donor acceptors increases the probability of hydrate and solvate formation
.
Hydrates are known to dissolve more slowly than anhydrous free crystals and require special storage conditions, making the manufacture of APIs and finished drugs more complex
.

(3) From the perspective of the delivery strategy of preclinical drugs, the solubility of drugs can be improved by adjusting the pH, but this method is limited to ionizable compounds
.
About 70% of FDA-approved oral molecules are ionizable compounds, a proportion that has remained stable in recent years, suggesting that pH and salt formation are important strategies
for drug delivery.

(4) molecules for cLogP> 4 are generally suitable for lipid drug delivery strategies; When cLogP> 5, molecules can use the lymphatic system to increase bioavailability
.
In addition to this, the melting point of the drug increases in 2011-2020 (Fsp3 decreases and HBA ), suitable for particle size reduction technology to improve solubility
.
But in some cases, the apparent solubility (nanometer size) of the drug needs to be changed, because drugs with higher melting points are more resistant to changes
in crystal morphology during shrinking.

6

Summary

This article mainly analyzes the changes in the nature of oral drugs approved by FDA from 1 900 to 2020 from the perspective of De vMA.
The only important property that has not changed is HBD, which is important
for the cellular permeability and lattice energy of compounds.
Before the successful development of a drug, D evMA evaluation in the early stage of development can help improve the speed of development and reduce the risk of
failure from the perspective of drug development.

This article focuses on the first part of the review of "Trends in small molecule drug properties: A developability molecule assessment perspective": Physicochemical properties vs Drug approval year, the remaining two will be covered
in the next issue.

References (swipe up or down to see more).

[1] Drug-like properties: Concepts, Structural Design and Methods (2nd edition of the original work).
Translated by Bai Renren

[2] Agarwal P, et al.
Drug Discov Today.
2022.
doi: 10.
1016/j.
drudis.
2022.
103366.

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