Synthesis, structure-activity relationship study and molecular modeling of triazolo[4,5-d]pyrimidines targeting an intracellular allosteric binding site of various chemokine receptors.

A previously reported triazolo[4,5-d]pyrimidine analogue displaying dual CCR7/CXCR2 antagonism was subjected to an optimisation campaign aiming at the discovery of potent and selective CCR7 antagonists. A range of substituted thiol groups was introduced at position 5 of the triazolo[4,5-d]pyrimidine core. In addition, a scaffold hopping approach was pursued yielding three novel skeletons. Unfortunately, none of these modifications led to improved CCR7 antagonistic potency or selectivity, when compared to the original lead compound. A broad chemokine receptor screening revealed that these originally CCR7/CXCR2 antagonists display very pronounced CCR2 antagonism. Finally, molecular modeling was applied in order to rationalize these experimental findings.