Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of βII tryptase

Tryptase is a serine protease implicated in the etiology of asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified β-amidoester benzamidines as potent inhibitors of recombinant human βII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides 16.