title: Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase.
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.
authors.affiliation: Drug Innovation and Approval, Aventis Pharmaceuticals, 1041 Route 202-206, Mail Stop N-103A, Bridgewater, NJ 08807-6800, USA. julian.levell@aventis.com
authors.forename: Julian
authors.initials: J
authors.lastname: Levell
authors.forename: Peter
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authors.lastname: Astles
authors.forename: Paul
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authors.lastname: Eastwood
authors.forename: Jennifer
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authors.lastname: Cairns
authors.forename: Olivier
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authors.lastname: Houille
authors.forename: Suzanne
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authors.lastname: Aldous
authors.forename: Gregory
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authors.lastname: Merriman
authors.forename: Brian
authors.initials: B
authors.lastname: Whiteley
authors.forename: James
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authors.lastname: Pribish
authors.forename: Mark
authors.initials: M
authors.lastname: Czekaj
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Sebastien
authors.initials: S
authors.lastname: Maignan
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Guilloteau
authors.forename: Alain
authors.initials: A
authors.lastname: Dupuy
authors.forename: Jane
authors.initials: J
authors.lastname: Davidson
authors.forename: Trevor
authors.initials: T
authors.lastname: Harrison
authors.forename: Andrew
authors.initials: A
authors.lastname: Morley
authors.forename: Simon
authors.initials: S
authors.lastname: Watson
authors.forename: Garry
authors.initials: G
authors.lastname: Fenton
authors.forename: Clive
authors.initials: C
authors.lastname: McCarthy
authors.forename: Joseph
authors.initials: J
authors.lastname: Romano
authors.forename: Rose
authors.initials: R
authors.lastname: Mathew
authors.forename: Darren
authors.initials: D
authors.lastname: Engers
authors.forename: Michael
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authors.lastname: Gardyan
authors.forename: Keith
authors.initials: K
authors.lastname: Sides
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kwong
authors.forename: Joseph
authors.initials: J
authors.lastname: Tsay
authors.forename: Sam
authors.initials: S
authors.lastname: Rebello
authors.forename: Liduo
authors.initials: L
authors.lastname: Shen
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Luo
authors.forename: Odessa
authors.initials: O
authors.lastname: Giardino
authors.forename: Heng-Keang
authors.initials: HK
authors.lastname: Lim
authors.forename: Keith
authors.initials: K
authors.lastname: Smith
authors.forename: Henry
authors.initials: H
authors.lastname: Pauls
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects; D012697:Serine Endopeptidases / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053802:Tryptases
chemical_list: D000577:Amides; D065427:Factor Xa Inhibitors; D010880:Piperidines; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D012697:Serine Endopeptidases; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases