Novel tactics for designing water-soluble molecules in drug discovery

Walker, Michael

doi:10.1517/17460441.2014.960839

Cited by 49 publications

(51 citation statements)

References 69 publications

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“…Aqueous solubility is a key physicochemical property of molecules, influencing ease of synthesis and purification, chemical-biological properties, functions of materials, effect on the environment, and so on 1 – 3 . For example, from the viewpoint of drug development, candidate compounds possessing sufficient aqueous solubility are considered to offer a relatively low risk of failure 4 – 7 .…”

Section: Introductionmentioning

confidence: 99%

Photo-enhanced Aqueous Solubilization of an Azo-compound

Ishikawa

Ohzono

Yamaguchi

et al. 2017

Sci Rep

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We previously showed that disruption of intermolecular interactions, e.g., by lowering the molecular planarity and/or introducing bent structures, improves the aqueous solubility of compounds, and based upon that work, we hypothesized that azobenzene trans-to-cis photoswitching could also be utilized to enhance the aqueous solubility of compounds. Here, we demonstrate that UV/visible light irradiation can reversibly switch the aqueous solubilization of an anti-cancer candidate drug, a low-molecular-weight kinase inhibitor bearing an azobenzene moiety. The increase of solubilization associated with UV-induced trans-to-cis conversion may have clinical relevance, because the time-scale of thermal cis-to-trans reversion at 37 °C is longer than that of oral absorption.

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Section: Introductionmentioning

confidence: 99%

Photo-enhanced Aqueous Solubilization of an Azo-compound

Ishikawa

Ohzono

Yamaguchi

et al. 2017

Sci Rep

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“…This structural feature provides large polar surface area and relative structural rigidity. The piperazine moiety can often function as both hydrogen bond acceptor and donor and lead to improved potency, selectivity, water solubility, oral bioavailability, and ADME (absorption, distribution, metabolism, and excretion) properties 3 . Similarly, other 1,4-diazo heterocycles such as 1,4-diazepanes and 1,4-diazocanes are important structural motifs in bioactive molecules.…”

Section: Introductionmentioning

confidence: 99%

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Adhikari

Xia

et al. 2018

Nat Commun

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Saturated 1,4-diazo heterocycles including piperazines, 1,4-diazepanes, and 1,4-diazocanes, are highly important for therapeutic development, but their syntheses are often tedious. We describe here an amphoteric diamination strategy to unite readily available 1,2-, 1,3- or 1,4-diamine derivatives with electron-deficient allenes via a formal [n + 2] (n = 4, 5, 6) cyclization mode to produce the corresponding 1,4-diazo heterocycles in just one step. This strategy features mild reaction conditions, high functional group tolerance, and scalability (gram scale). The reagents used are cheap and readily available and no transition metal catalysts are needed. More sophisticated products containing trifluoromethyl group or bicyclic ring systems can be accessed via a one-pot procedure as well. Our mechanistic studies support that formation of mono-iodinated or chlorinated diamine intermediates is important for the desired transformation and the commonly proposed chloride-iodide exchange process and a radical N−C bond formation is unlikely when the combination of NCS/KI is used.

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“…The design of compounds with suitable physicochemical properties is of paramount importance in drug discovery, since working in the optimal space may lead to improved pharmacokinetic and safety profiles (Arnott and Planey, 2012;Gleeson, 2008;Leeson and Springthorpe, 2007;Manallack et al, 2013;Ritchie et al, 2011;Wager et al, 2010;Walker, 2014). Among the relevant characteristics of a compound, lipophilicity is considered a very significant parameter and, commonly, it is expressed as the partition coefficient between n-octanol and aqueous phase (log Po/w).…”

Section: Introductionmentioning

confidence: 99%

Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs

Port

Bordas

Enrech

et al. 2018

European Journal of Pharmaceutical Sciences

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In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log P) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log P values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form.

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Novel tactics for designing water-soluble molecules in drug discovery

Cited by 49 publications

References 69 publications

Photo-enhanced Aqueous Solubilization of an Azo-compound

Photo-enhanced Aqueous Solubilization of an Azo-compound

Expedient syntheses of N-heterocycles via intermolecular amphoteric diamination of allenes

Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log P o/w ) of neutral, acidic, basic, amphoteric, and zwitterionic drugs

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