209899-59-2Relevant articles and documents
Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: Novel, potent, selective, and orally bioavailable inhibitors of βII tryptase
Levell, Julian,Astles, Peter,Eastwood, Paul,Cairns, Jennifer,Houille, Olivier,Aldous, Suzanne,Merriman, Gregory,Whiteley, Brian,Pribish, James,Czekaj, Mark,Liang, Guyan,Maignan, Sebastien,Guilloteau, Jean-Pierre,Dupuy, Alain,Davidson, Jane,Harrison, Trevor,Morley, Andrew,Watson, Simon,Fenton, Garry,McCarthy, Clive,Romano, Joseph,Mathew, Rose,Engers, Darren,Gardyan, Michael,Sides, Keith,Kwong, Jennifer,Tsay, Joseph,Rebello, Sam,Shen, Liduo,Wang, Jie,Luo, Yongyi,Giardino, Odessa,Lim, Heng-Keang,Smith, Keith,Pauls, Henry
, p. 2859 - 2872 (2007/10/03)
Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase β is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human 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.
