Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators

Kolarič A, Švajger U, Tomašič T, Brox R, Frank T, Minovski N, Tschammer N, Anderluh M (2018)

Publication Type: Journal article

Publication year: 2018

Journal

European Journal of Medicinal Chemistry Elsevier

Book Volume: 154

Pages Range: 68-90

DOI: 10.1016/j.ejmech.2018.05.013

Abstract

Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors.

Authors with CRIS profile

Regine Brox Lehrstuhl für Pharmazeutische Chemie Theresa Frank Lehrstuhl für Biochemie Nuska Tschammer Lehrstuhl für Pharmazeutische Chemie

Involved external institutions

University of Ljubljana (UL) / Univerza v Ljubljani SI Slovenia (SI) Blood Transfusion Centre of Slovenia (BTC d.d.) SI Slovenia (SI) National Institute of Chemistry / Kemijski Inštitut SI Slovenia (SI)

How to cite

APA:

Kolarič, A., Švajger, U., Tomašič, T., Brox, R., Frank, T., Minovski, N.,... Anderluh, M. (2018). Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators. European Journal of Medicinal Chemistry, 154, 68-90. https://dx.doi.org/10.1016/j.ejmech.2018.05.013

MLA:

Kolarič, Anja, et al. "Insight into structural requirements for selective and/or dual CXCR3 and CXCR4 allosteric modulators." European Journal of Medicinal Chemistry 154 (2018): 68-90.

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