Potent, Nonpeptide Inhibitors of Human Mast Cell Tryptase. 2. Investigation of the Carboxamide Portion of Spirocyclic Piperidine Amides

We have explored a series of spirocyclic piperidine amide derivatives with respect to the N-acyl portion ( viz. 6) for inhibition of tryptase. Thus, we identified analogues 6nn and 600 as potent tryptase inhibitors (IC50 < 10 nM) with excellent selectivity vs. trypsin. Other interesting compounds (IC50 = 10-20 nM) in this chemical series are 6k, 6m, 6ff, and 6bbb. X-ray co-crystal structures of 6nn.tryptase and 6pp.tryptase are reported.