Lipophilicity has a significant impact on many parameters that determine the exposure and efficacy of non-conjugated drugs。Nonetheless, analysis of large amounts of drug data has shown that lipophilicity does not have a consistent directed effect on dose. This can be rationally explained based on the interaction of the effects of lipophilicity on individual parameter values in the pharmacokinetic equation. Since lipophilicity plays a dominant role in these parameters, it weakens the effectiveness of strategies that target a specific range of drug parameters。The authors' research facilities no longer use the common method of screening drugs with low intrinsic clearance in vitro to screen drugs with high unbinding exposures in vivo. On the contrary, the author arguesReduce bias for lipophilicity by optimizing the ratio of key parameters for dose control。The authors believe that this will allow for the exploration of a wider physicochemical space, thereby improving the efficiency of drug discovery.
Table 1Summary of the effects of lipophilicity on drug design parameters.
Drug affinity has long been known for itsenthalpywithEntropycomponent, both of which contribute to the overall negative free energy (δg) associated with target binding. In the process of efficacy optimization, enthalpy-derived interactions are more likely to be target-selective than entropy-solubilizing effects of lipophilic ones. Increasing efficacy through lipophilicity can also lead to a decrease in overall druggability, negatively affecting certain PK parameters that affect non-binding exposure. This view is confirmed by data from internal drug discovery and development programs presented hereThat is, it is possible to increase the efficacy by increasing lipophilicity, but this increase is often offset by a decrease in non-binding exposure. However, the authors do not believe that lipophilicity-enhancing efficacy is counterproductive, but rather that this trade-off simply enables the authors to take advantage of the broad physicochemical space and more effectively optimize all necessary and interrelated parameters.
In drug design, due to the need to minimize the likelihood of adverse pharmacological or toxicological effectsOff-target efficacyClearly a matter of concern. It is generally accepted that the number of off-targets reported by extensive in vitro back-screens tends to increase with increasing lipophilicity. This suggestsAs lipophilicity increases, so does the overall off-target messiness and risk。However, these data should not be considered in isolation, but should be considered in conjunction with the on-target potency required for the lipophilic compound to achieve the desired pharmacological effect at acceptable doses. From this perspective, lipophilicity may affect some of the on-target and extra-target titers in a similar way, hence the pairSelective characteristicsThe impact is minimal. Therefore, caution must be exercised when considering cut-offs based only on non-target titer screening values, as this may have unintended consequences, iePreference is given only to more polar molecules, thereby reducing their activity on the target
As with efficacy, many of the individual parameters that control exposure to non-conjugated drugs also have lipophilic or entropic components. Therefore,As lipophilicity increases, so do the values of VSS, U, and CLU, resulting in a decrease in non-binding exposure. For example, highly lipophilic compounds will certainly have a larger VSS,U (i.e., a larger drug reservoir) because they have extensive non-specific binding in vivo. Similarly, highly lipophilic compounds typically have higher CLU because the dissolving effect enhances their interaction with the lipophilic active site of the xeno-eliminating enzyme transporter. In each of the above cases, other factors also contribute to an increase in its value. For example, specific binding interactions with albumin or cathepsin lipids, as well as other distributional effects, can further enhance VSS,U;Compounds with low lipophilicity may also have high CLU when their enzyme elimination is very rapid at the soft spot of metabolism. However, given the important directional effects of lipophilicity on CLU and VSS,U, the authors could look at the effect of lipophilicity on non-binding exposure from an important perspective, which was not significant based on the total drug parameters CL and VSS.
Within a reasonable drug-like space, the effect of lipophilicity is less pronounced when all parameters are appropriately factored into the effective dose. As the author has already demonstrated,The effect of lipophilicity on many individual PK parameters can be considerable;But they have a tendency to cancel each other out, which the authors have shown can be reasonably explained in terms of the interrelationships in the PK equation. While it is true that an increase in LUs and VSS,U due to lipophilicity reduces non-binding exposure in vivo, this can be balanced by an increase in non-binding titers due to lipophilicity in many of the findings. The effect of lipophilicity on multiple parameters also explains why lipophilicity has no deabilitable effect on T12 and the inability to modulate T12 when targeting low CLU or high VSS,U alone. Similarly, while lipophilicity has a significant directional effect on many individual parameters that determine oral bioavailability (f), the authors also observed that acceptable fs can be achieved over a wide range of lipophilicity.
In the process of drug development, strategies to increase in vivo non-binding exposure using in vitro clint, small VSS,U, or reduced lipophilicity have been proposed and adopted to varying degrees. While these methods are often successful in increasing exposure to non-conjugated drugs, the authors found themInability to improve the efficiency of optimizing the dose, because they are not taken into accountThere is a decreasing trend in efficacy with the decrease in lipophilicity。This, according to the authors, explains why past drugs, as well as the authors' own clinical candidates, are not significantly biased"Low"CLU (Figure 3), although strategies to target this issue have been very popular over the past two decades. These methods may also inadvertently limit the range of physicochemical spaces studied, as they are inherently biased towards compounds that are less lipophilic.
For these reasons, the author's laboratoryIn vitro metabolic stability is no longer used as a method for early screening, but a specific preference is given to selecting those who are expected to have"Low"clint, clu, or compounds with high non-binding exposure. While the data from these assays still play an important role, the authors believe that the right decisions can only be made if they are combined with other data. For example, while species differences in in in vitro metabolic rate are important for human clearance using isomerism, IVIVC, or other methods, there should be no pre-defined target values or ranges for these data.
The author believesFocus on optimizing the ratio of parameters that directly affect the effective dosehas the advantage of taking into account the entropy or non-selective effects of lipophilicity on individual parameters. A few key ratios that produce counteracting effects due to lipophilicity are oral absorption (permeability vs. soluness), liver extraction (Clint, H vs. FU), Cmax,U-based target engagement (VSS, U vs. non-binding titer), AUCU-based steady-state target engagement (CLU vs. non-binding titer), effective half-life (CLU vs. VSS,U), and non-target selectivity ( target EC50 vs. off-target EC50). When attempting to adjust these ratios, it should be assumed that a non-specific change in one parameter due to lipophilicity may lead to a potentially countervailing change in other parameters, rather than a random change. Therefore,While the target range of a single parameter can often be achieved most quickly by adjusting lipophilicity, lipophilicity alone often has little effect on optimizing the proportion of parameters that are important. Data from an internal antiviral discovery project cited here (Figure 7) demonstrate the ability to achieve ideal parameter ratios over a wide range of lipophilicity and a single range of values for CLU, VSS, U, FU, unbound titer and unbound exposure, while a specific range for a single parameter would incorrectly screen for many viable lead compounds. The range of acceptable values for individual parameters of drugs sold on the market and clinical candidates within the authors is even greater.
Figure 7The balance of pharmacokinetic parameters in individual rats of the antiviral target resulted in a human dose of <500 mg bid, achieved over a wide range of lipophilicity (unbound potency calculated from the EC (50) cell assay).
Exploring the vast physicochemical space increases efficiency and overall success
It makes sense to modulate lipophilicity in drug design. It is very important to aim for a good physical and chemical space that is consistent with the parameter values of drugs-like drugs to improve the overall development capability。Polar compounds are generally poorly absorbed or intracellular due to their lack of membrane permeability and instability. This also creates uncertainty in their profile due to the greater likelihood of transporter involvement in the absorption, distribution, and elimination, while the optimization of half-lives becomes more difficult due to the lack of drug storage. On the other hand, highly lipophilic compounds can also result in low or unstable absorption due to very low solubility and are difficult to characterize due to the effect of non-specific binding on in vitro and in vivo measurements. In both cases,Tweaking lipophilicity to a chemical space that is easier to develop can improve the overall success rate.
While modulating lipophilicity within a good drug-like space may not lead to better results per se, it can provide different opportunities to address compound deficiencies identified during optimization. As a result, projects with more chemical diversity are generally considered to have a higher overall probability of success than projects with less chemical diversity. The authors reviewed data from marketed drugs, as well as compounds in the authors' own discovery and development programs, and the results showed consistency with past and present drug discovery efforts. These data do not support the expectation that compounds with low lipophilicity (high non-binding exposure) have a clear advantage. Instead, past efforts have led to the distribution of drugs and drug candidates in a vast physicochemical space, suggesting that lipophilicity should not be favored in a rational drug-like space. Therefore, the author believesIn general, strategies that limit chemical space but do not provide a clear advantage should be avoided.
Cl(u), V(ss,U) and unbound potency are widely distributed across a range of lipophiles;However, these compounds can be efficiently balanced, so that optimized compounds (defined by a ** dose of < 500 mg bid) can be identified over a wide range of physicochemical spaces. In addition, the lead compounds identified by the discovery team to enter the initial preclinical safety assessment also cover different physicochemical spaces. However, the initial strategy of this program was to target high unbound exposure (INT) by screening for low in vitro CL, which led to the discovery of lead compound A with relative polarity (Table 3). However, over the course of the project, it was found that this strategy arbitrarily limited the chemical space because it did not properly consider the potential of more lipophilic compounds to increase potency, sufficient to compensate for the lower unbound exposure at similar doses.
Table 3Lead compounds of antiviral targets exhibit a common parametric relationship, thereby counteracting the effects of unbound exposure and potency.
In conclusion, there seems to be a consensus on the importance of balancing properties in drug design. However, the authors argue that an oversimplified strategy can bias the range of individual parameters or have a directional impact on parameter improvement, reducing the efficiency of achieving this goal. While the effects of lipophilicity on individual parameters are well documented in the literature and are generally recognized, the extent to which these effects tend to be counteracted when fully integrated into the final effective dose does not appear to be underappreciated. This includes the two main factors of any optimization strategy, namely drug potency and in vivo drug exposure. **The correlation between dose and in vitro efficacy has been shown to be relatively weak, and as the practice of incorporating ADME properties into drug design has become more common, there have been fewer attempts to improve efficacy alone.
However, as the authors observe and discuss here, there appears to be little correlation between unconjugated exposure and the ability to achieve an acceptable dose. Nonetheless, strategies to provide high non-binding exposure by adjusting individual parameters such as decreasing clint and or drug binding (whether FU or VSS, U (16)) remain. The author believesFully considering the relationship between the elimination, distribution and efficacy of nonconjugated drugs plays an important role in improving the design strategy。This is where the challenge and complexity of drug design lies: when many parameter values are not randomly distributed, the relative values between them need to be optimized. Strategies that deliberately focus on the ratio of specific parameters that affect the effective dose will take this reality into account more effectively, while preserving a wide physicochemical space in order to find the optimal balance of all properties. While these strategies may seem more complex and more difficult to execute, they are also more likely to be more successful and efficient in drug development, based on the authors' experience.
Reference: Integrating the impact of lipophilicity on potency and pharmacokinetic parameters enables the use of diverse chemical space during small molecule drug optimization
randy r. miller, maria madeira, harold b. wood, wayne m. geissler, conrad e. raab, and iain j. martin
journal of medicinal chemistry
doi: 10.1021/acs.jmedchem.9b01813
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