Synthesis and evaluation of 4-substituted benzylamine derivatives as beta-tryptase inhibitors.
Since beta-tryptase is considered a critical mediator of asthma, potent tryptase inhibitors may be useful as new agents for the treatment of asthma. We investigated 4-substituted benzylamine derivatives and obtained M58539 (15h) as a potent inhibitor of beta-tryptase (IC50 = 5.0 nM) with high selectivity against other serine proteases, low molecular weight, clog P value less than 5, lack of amidino and guanidino groups, and independence of Zn2+ ion.
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd, 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. ymiya@mochida.co.jp
Yutaka
Y
Miyazaki
Yutaka
Y
Kato
Tadashi
T
Manabe
Hiroyasu
H
Shimada
Masashi
M
Mizuno
Takayuki
T
Egusa
Munetaka
M
Ohkouchi
Ikuya
I
Shiromizu
Tomokazu
T
Matsusue
Ichiro
I
Yamamoto
D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007477:Ions / Q000737:chemistry; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D053802:Tryptases; D015032:Zinc / Q000737:chemistry / Q000494:pharmacology
D001596:Benzylamines; D007477:Ions; D009281:Naphthalenes; D015842:Serine Proteinase Inhibitors; C031721:naphthalene; C030796:benzylamine; D012697:Serine Endopeptidases; D053802:Tryptases; D015032:Zinc