Inappropriate activation of endosomal
TLR7 and TLR8 occurs in several
autoimmune diseases, in particular systemic lupus erythematosus (SLE).
Herein, the development of a TLR8 antagonist competition assay and
its application for hit generation of dual TLR7/8 antagonists are
reported. The structure-guided optimization of the pyridone hit 3 using this biochemical assay in combination with cellular
and TLR8 cocrystal structural data resulted in the identification
of a highly potent and selective TLR7/8 antagonist (27) with in vivo efficacy. The two key steps for optimization
were (i) a core morph guided by a TLR7 sequence alignment to achieve
a dual TLR7/8 antagonism profile and (ii) introduction of a fluorine
in the piperidine ring to reduce its basicity, resulting in attractive
oral pharmacokinetic (PK) properties and improved TLR8 binding affinity.
Inappropriate activation of TLR7 and TLR8 is linked to several autoimmune diseases, such as lupus erythematosus. Here we report on the efficient structure-based optimization of the inhibition of TLR8, starting from a co-crystal structure of a small screening hit. Further optimization of the physicochemical properties for cellular potency and expansion of the structure− activity relationship for dual potency finally resulted in a highly potent TLR7/8 antagonist with demonstrated in vivo efficacy after oral dosing.
Regioselective Nitration of 3-Fluoro-2-Substituted Benzoic Acids. -The partially excellent regioselectivities of the nitration reaction is rationalized in most cases using Fukui indices of local nucleophilicity. -(HURTH*, K.; JACQUIER, S.; LEHMANN, H.; WILCKEN, R.; Tetrahedron Lett. 56 (2015) 22, 2860-2862, http://dx.
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