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PDBsum entry 2bm2
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References listed in PDB file
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Key reference
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Title
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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
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J.Levell,
P.Astles,
P.Eastwood,
J.Cairns,
O.Houille,
S.Aldous,
G.Merriman,
B.Whiteley,
J.Pribish,
M.Czekaj,
G.Liang,
S.Maignan,
J.P.Guilloteau,
A.Dupuy,
J.Davidson,
T.Harrison,
A.Morley,
S.Watson,
G.Fenton,
C.Mccarthy,
J.Romano,
R.Mathew,
D.Engers,
M.Gardyan,
K.Sides,
J.Kwong,
J.Tsay,
S.Rebello,
L.Shen,
J.Wang,
Y.Luo,
O.Giardino,
H.K.Lim,
K.Smith,
H.Pauls.
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Ref.
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Bioorg Med Chem Lett, 2005,
13,
2859-2872.
[DOI no: ]
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PubMed id
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Abstract
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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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