Orally bioavailable competitive CCR5 antagonists |
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Authors: | Thoma Gebhard Nuninger François Schaefer Marc Akyel Kayhan G Albert Rainer Beerli Christian Bruns Christian Francotte Eric Luyten Marcel MacKenzie Duncan Oberer Lukas Streiff Markus B Wagner Trixie Walter Hansrudolf Weckbecker Gisbert Zerwes Hans-Guenter |
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Institution: | Novartis Institutes for BioMedical Research, Lichtstrasse 35, WSJ-507.4.12, CH-4056 Basel, Switzerland. gebhard.thoma@pharma.novartis.com |
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Abstract: | The chemokine receptor CCR5 plays an important role in inflammatory and autoimmune disorders as well as in transplant rejection by affecting the trafficking of effector T cells and monocytes to diseased tissues. Antagonists of CCR5 are believed to be of potential therapeutic value for the disorders mentioned above and HIV infection. Here we report on the structure-activity relationship of a new series of highly potent and selective competitive CCR5 antagonists. While all compounds tested were inactive on rodent CCR5, this series includes compounds that cross-react with the cynomolgus monkey (cyno) receptor. One of these compounds, i.e., 26n, has good PK properties in cynos, and its overall favorable profile makes it a promising candidate for in vivo profiling in transplantation and other disease models. |
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