Author/Editor		Dolšak, Ana; Šribar, Dora; Scheffler, Alexander; Grabowski, Maria; Švajger, Urban; Gobec, Stanislav; Holze, Janine; Weindl, Günther; Wolber, Gerhard; Sova, Matej
Title		Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators
Type		članek
Vol. and No.		, št. Vol. 225
Publication year		2021
Volume		str. 1-17
ISSN		0223-5234 - European Journal of Medicinal Chemistry
Language		eng
Abstract		Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure-activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 [micro]M represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
Descriptors		Avtoimunske bolezni Farmacevtska kemija
Keywords		Toll-u podobni receptorji modulatorji imunomodulatorji avtoimunske motnje pirimidini molekulska dinamika Toll-like receptors TLR8 modulators pyrimidines immunomodulation autoimmune disorders