The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

Ferenczy, György G.; Keserü, György M.

doi:10.4155/fmc.15.63

Cited by 9 publications

(2 citation statements)

References 66 publications

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“…The strategy is to discriminate, as far as possible, between the enthalpic efficiency and entropy profile (ΔH driven > ΔS driven) but to have both and consequently to have a good balanced affinity between these two thermodynamic functions. 32,33 In addition, we chose this site for substitution due to the easy chemical transformations. Thus, as shown in Scheme 1, the synthesis of ring A analogues began with a simple Suzuki cross-coupling reaction between 5-bromo-7-azaindole 5 and heteroaryl/aryl boronic acids (6a−s), 34,35 which gave 5-aryl/hetroaryl substituted 7-azaindoles (7a−s) in good yields (60−95%).…”

Section: ■ Introductionmentioning

confidence: 99%

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

et al. 2017

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In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

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Section: ■ Introductionmentioning

confidence: 99%

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

et al. 2017

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“…Compounds tend to be larger and increasingly hydrophobic with improving affinity. This is, however, not beneficial, since large and hydrophobic compounds have unfavorable physicochemical properties and are more prone to suboptimal ADME profile as it was shown by the comparison of compounds from various stages of the discovery process [45,[48][49][50][51]. It was also shown that property inflation is a general phenomenon and is basically independent from the hit identification strategy, rather it could be traced back to optimization practices [7].…”

Section: Thermodynamics and Drug-like Propertiesmentioning

confidence: 99%

Thermodynamic profiling for fragment-based lead discovery and optimization

Ferenczy

Keserü

2019

Expert Opinion on Drug Discovery

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Introduction: The enthalpic and entropic components of the ligand-protein binding free energy reflect the type and quality of the interactions and relate to the physicochemical properties of the ligands. These findings have significance in medicinal chemistry optimizations since they suggest that the thermodynamic profiling of the binding may help monitor and control the unfavorable size and hydrophobicity increase typically accompanying affinity improvements and leading to suboptimal pharmacokinetic properties.Areas covered: This review describes the ligand-protein binding event in terms of elementary steps, their associated interactions, and their enthalpic and entropic consequences. The relationships among the breaking and forming interactions, the binding thermodynamic profile, and the physicochemical properties of the ligands are also discussed. Expert opinion: Analysis of the size dependence of available affinity and favorable enthalpy highlights the limitation of the simultaneous optimization of these quantities. Indeed, moderate, rather than very high affinities can be conciliated with favorable physicochemical and pharmacokinetic profiles as it is supported by the affinity range of historical oral drugs. Although thermodynamic quantities are not suitable endpoints for medicinal chemistry optimizations owing to the complexity of the binding thermodynamics, thermodynamic profiling together with structural studies can be advantageously used to understand the details of the binding process and to optimize it.

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The Impact of Lipophilicity in Drug Discovery: Rapid Measurements by Means of Reversed-Phase HPLC

Giaginis

Tsopelas

Tsantili‐Kakoulidou

2018

Methods in Molecular Biology

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Lipophilicity constitutes a vital physicochemical property in drug design as it is connected with pharmacodynamic and pharmacokinetic properties as well as toxicological aspects of candidate drugs. Traditional partitioning experiments to determine n-octanol-water coefficients are laborious and time-consuming, while they cannot be reliably performed for highly lipophilic or compounds undergoing degradation. Alternatively, lipophilicity of candidate drugs can be accurately and reproducibly determined using reversed-phase liquid chromatography. In this chapter, the details of protocols for lipophilicity assessment using reversed-phase HPLC, under conditions which provide the best simulation of n-octanol-water partition coefficients, are described.

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The Impact of Binding Thermodynamics on Medicinal Chemistry Optimizations

Cited by 9 publications

References 66 publications

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

Design of Novel 3-Pyrimidinylazaindole CDK2/9 Inhibitors with Potent In Vitro and In Vivo Antitumor Efficacy in a Triple-Negative Breast Cancer Model

Thermodynamic profiling for fragment-based lead discovery and optimization

The Impact of Lipophilicity in Drug Discovery: Rapid Measurements by Means of Reversed-Phase HPLC

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