Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase |
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Authors: | 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 |
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Institution: | Drug Innovation and Approval, Aventis Pharmaceuticals, 1041 Route 202-206, Mail Stop N-103A, Bridgewater, NJ 08807-6800, USA. julian.levell@aventis.com |
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Abstract: | 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 beta 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 beta-amidoester benzamidines as potent inhibitors of recombinant human betaII 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. |
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