Design, synthesis and SAR analysis of potent BACE1 inhibitors: Possible lead drug candidates for Alzheimer's disease.

Tarazi, Hamadeh; Odeh, Raed Abu; Al-Qawasmeh, Raed; Yousef, Imad Abu; Voelter, Wolfgang; Al-Tel, Taleb H

Tarazi, Hamadeh; Odeh, Raed Abu; Al-Qawasmeh, Raed; Yousef, Imad Abu; Voelter, Wolfgang; Al-Tel, Taleb H.

Afiliación

Tarazi H; College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
Odeh RA; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; College of Health Sciences, Department of Medical Laboratory Sciences, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates.
Al-Qawasmeh R; Department of Chemistry, The University of Jordan, Amman 11942, Jordan.
Yousef IA; College of Arts and Sciences, Department of Biology, Chemistry and Environmental Sciences, American University of Sharjah, Sharjah, United Arab Emirates.
Voelter W; Interfakultäres Institut für Biochemie, Eberhard-Karls-Universität Tübingen, Hoppe-Seyler-Straße 4, D-72076 Tübingen, Germany.
Al-Tel TH; College of Pharmacy, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates; Sharjah Institute for Medical Research, University of Sharjah, PO Box 27272, Sharjah, United Arab Emirates. Electronic address: taltal@sharjah.ac.ae.

Eur J Med Chem ; 125: 1213-1224, 2017 Jan 05.

Article en En | MEDLINE | ID: mdl-27871037

RESUMEN

We have identified potent isophthalic acid derivatives armed with imidazol and indolyl groups as potent ß-secretase inhibitors. The most effective analogs demonstrated low nano-molar potency for the BACE1 (ß-secretase cleaving enzyme) as measured by FRET (Fluorescence Resonance Energy Transfer) and cell-based (ELISA) assays. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on previously reported hydroxyethylene transition state inhibitor derived from isophthalic acid I. In the FRET assay, the most potent compound, 10a, displayed an IC50 value for BACE1 of 75 nM, and exhibited cellular activity with an EC50 value of 0.81 µM. On the other hand, compound 11b was found to be the most potent compound in the cell-based assay with an EC50 value of 0.29 µM.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico; Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores; Ácido Aspártico Endopeptidasas/antagonistas & inhibidores; Inhibidores Enzimáticos/química; Inhibidores Enzimáticos/farmacología; Ácidos Ftálicos/química; Ácidos Ftálicos/farmacología; Enfermedad de Alzheimer/metabolismo; Secretasas de la Proteína Precursora del Amiloide/química; Secretasas de la Proteína Precursora del Amiloide/metabolismo; Ácido Aspártico Endopeptidasas/química; Ácido Aspártico Endopeptidasas/metabolismo; Línea Celular; Diseño de Fármacos; Inhibidores Enzimáticos/síntesis química; Humanos; Imidazoles/síntesis química; Imidazoles/química; Imidazoles/farmacología; Simulación del Acoplamiento Molecular; Ácidos Ftálicos/síntesis química; Relación Estructura-Actividad

Palabras clave

Alzheimer's disease; Isophthalic acid derivatives; Molecular modeling; Structure activity relationship; Structure-based drug design; Transition state mimics; ß-secretase inhibitors

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ácidos Ftálicos / Ácido Aspártico Endopeptidasas / Inhibidores Enzimáticos / Secretasas de la Proteína Precursora del Amiloide / Enfermedad de Alzheimer Límite: Humans Idioma: En Revista: Eur J Med Chem Año: 2017 Tipo del documento: Article País de afiliación: Emiratos Árabes Unidos Pais de publicación: Francia

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