Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?

The tetrameric folding of β-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for β-tryptase.