Lipophilicity and Its Relationship with Passive Drug Permeation

Liu, Xiangli; Testa, Bernard; Fahr, Alfred

doi:10.1007/s11095-010-0303-7

Cited by 355 publications

(252 citation statements)

References 112 publications

Supporting

Mentioning

241

Contrasting

Unclassified

Order By: Relevance

“…14 In support of this notion it was also found that logP oct-alk correlates with brain penetration and oral absorption. 15,16 Recent systematic work incorporating IMHB considerations in drug design has been published by Kuhn and coworkers. 17 On the basis of pioneering work by Etter 18 and Bilton 19 and exhaustive searches of crystal structure databases, they derived propensities for IMHB formation of five-to eight-membered ring systems of relevance in drug discovery.…”

Section: Introductionmentioning

confidence: 99%

“…The idea that logP oct-alk is informative of IMHB and the reports that logP oct-alk correlates with brain penetration and oral absorbtion 15,16 lead us to explore logP oct-tol (logP oct-tol = logP octlogP tol . [25][26][27][28][29] The investigation of IMHB by logP was proposed some time ago 30 , however this approach was not widely implemented mainly because the practical tools, both experimental and theoretical, to obtain logP alk data for large series of compounds were limited.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

View full text Add to dashboard Cite

This study demonstrates that logP oct-tol (difference between logPoctanol and logPtoluene) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates.We identified experimental protocols for acquiring reliable logP oct-tol values on a set of compounds representing IMHB motifs most prevalent in Medicinal Chemistry, mainly molecules capable of forming 6-, 7-member IMHB rings.Furthermore, computational logP oct-tol values obtained with COSMO-RS software provided a good estimate of experimental results and can be used prospectively to assess IMHB.The proposed interpretation method based on logP oct-tol data allowed categorization of the compounds into 2 groups -with high propensity to form IMHB and poor propensity or poor relevance of IMHB.The relative 1 H NMR chemical shift of an exchangeable proton was used to verify presence of IMHB and to validate the IMHB interpretation scheme.4

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

et al. 2013

View full text Add to dashboard Cite

show abstract

“…It has been shown that the difference between two log P values (log P) obtained in different biphasic systems for example octanol/water and alkane/water (log P oct-alk = log P oct -log P alk ), is informative of the solutes HBD properties (Abraham et al, 2010b) and thus useful in the prediction of drugs human fate (Liu et al, 2011). The recent interest for the application of log P oct-alk in the drug discovery process stimulated the research for the design and implementation of tools for its prediction (Caron and Ermondi, 2005) (Toulmin et al, 2008) (Kenny et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

The Block Relevance (BR) analysis supports the dominating effect of solutes hydrogen bond acidity on ΔlogPoct–tol

Ermondi

Visconti

Esposito

2014

European Journal of Pharmaceutical Sciences

View full text Add to dashboard Cite

“…La hidrofobicidad molecular fue incluida en los modelos QSAR mediante el coeficiente de partición n-octanol/agua (LogP o/w ), que mide la permeabilidad de las membranas biológicas hacia una molécula en particular. 42,43 Los LogP o/w fueron calculados utilizando la versión online del programa ALOGPS 2.1 siguiendo el esquema propuesto por Tetko y colaboradores. 44,45 Metodología QSAR La construcción de los modelos QSAR se llevó a cabo mediante el análisis de regresión lineal múltiple (MLR, por sus siglas en inglés) implementado en el software BuildQSAR.…”

Section: Metodología Computacionalunclassified

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

Guerra¹,

López²,

Figueredo³

et al. 2016

Química Nova

View full text Add to dashboard Cite

publicado na web em 06/05/2016 2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE. In the present work was performed a quantitative structure-activity relationship (QSAR) for a set of derivatives of 1,4-quinoxaline N-oxides with antichagasic activity based on reactivity descriptors from the frame conceptual DFT. QSAR models showed a good statistical quality and capacity internal prediction with R 2 > 0.6 and Q 2 > 0.5 respectively. QSAR model suggest that antichagasic activity of the studied compounds depends largely from the reactive behavior of N-oxide group (N-O). Also, reactivity descriptors showed that the N-oxide group is a reactive site in theses derivatives with nucleophilic characteristics. The results QSAR shed light on the understanding of the mechanism of action and design of new drugs based on derivatives of 1,4-di-N-oxides quinoxaline.Keywords: QSAR; Antichagasic; N-oxide group; Nucleophilic. INTRODUCCIONLa enfermedad de Chagas fue descubierta en 1909 por el medico brasileño Carlos Chagas mientras diagnosticaba a una joven paciente de dos años que presentaba parásitos en el torrente sanguíneo.1 Esta enfermedad, producida por el parásito protozoario Trypanosoma cruzi (T. cruzi), afecta actualmente entre 6 y 8 millones de personas en el mundo, 2 siendo endémica en América latina. No obstante, su incidencia en el continente europeo y algunos países de Norteamérica ha aumentado en los últimos años debido a los patrones de migración que provocan la diseminación de la enfermedad. 3,4 Aunque el principal modo de transmisión de T. cruzi hacia el ser humano ocurre por contacto con las heces de algunos hematófagos triatominos, 5 existen otros modos de infección asociados a transfusiones sanguíneas, 6 trasplantes de órganos, 7,8 contacto entre madre e hijo durante el parto, 9 y por vía oral. 10Con respecto a las manifestaciones clínicas, existen dos etapas que caracterizan la enfermedad de Chagas. La primera etapa comienza justo después de la infección (fase aguda), y aunque es asintomática, se han reportado casos con síntomas similares a los de una infección febril, dificultando así su correcto diagnóstico. 11La segunda etapa (fase crónica), que puede tardar hasta 15 años en aparecer, se caracteriza por cardiomiopatía dilatada 12,13 y afecciones del tracto digestivo 14 que representan un alto riesgo comprometiendo la vida de los pacientes. Desde el punto de vista farmacológico, el tratamiento actual de la enfermedad de Chagas se basa principalmente en dos fármacos nitro-heterocíclicos llamados Nifurtimox (Nfx) y benznidazol (Bz), descubiertos empíricamente entre 1960 y 1970; mostrando una efectividad en casi el 60% de los casos que son tratados durante la fase aguda. Sin embargo, el uso de Nfx y Bz para el tratamiento de la enfermedad durante la frase crónica es controversial debido a que estos nitro-heterociclos solo son eficaces contra la forma extracelular de T. cruzi que se desarrolla durante la fase aguda. Por lo tanto, la búsqueda de nuevos fármacos más...

show abstract

Lipophilicity and Its Relationship with Passive Drug Permeation

Cited by 355 publications

References 112 publications

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

The Block Relevance (BR) analysis supports the dominating effect of solutes hydrogen bond acidity on ΔlogPoct–tol

2D-QSAR ANALYSIS OF DERIVATIVES OF QUINOXALINE 1,4-DI-N-OXIDES WITH ACTIVITY AGAINST CHAGAS' DISEASE

Contact Info

Product

Resources

About