Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase.
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.
Levell
Julian
J
Drug Innovation and Approval, Aventis Pharmaceuticals, 1041 Route 202-206, Mail Stop N-103A, Bridgewater, NJ 08807-6800, USA. julian.levell@aventis.com
Astles
Peter
P
Eastwood
Paul
P
Cairns
Jennifer
J
Houille
Olivier
O
Aldous
Suzanne
S
Merriman
Gregory
G
Whiteley
Brian
B
Pribish
James
J
Czekaj
Mark
M
Liang
Guyan
G
Maignan
Sebastien
S
Guilloteau
Jean-Pierre
JP
Dupuy
Alain
A
Davidson
Jane
J
Harrison
Trevor
T
Morley
Andrew
A
Watson
Simon
S
Fenton
Garry
G
McCarthy
Clive
C
Romano
Joseph
J
Mathew
Rose
R
Engers
Darren
D
Gardyan
Michael
M
Sides
Keith
K
Kwong
Jennifer
J
Tsay
Joseph
J
Rebello
Sam
S
Shen
Liduo
L
Wang
Jie
J
Luo
Yongyi
Y
Giardino
Odessa
O
Lim
Heng-Keang
HK
Smith
Keith
K
Pauls
Henry
H
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
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