Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives
Hélène G Bazin1, Yufeng Li1, Juhienah K Khalaf1
1GlaxoSmithKline Vaccines, 553 Old Corvallis Road, Hamilton, MT 59840, USA.
Abstract:
We report the synthesis and biological evaluation of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a-g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFNα inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist.
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