Synthesis and evaluation of 4-substituted benzylamine derivatives as beta-tryptase inhibitors

Yutaka Miyazaki; Yutaka Kato; Tadashi Manabe; Hiroyasu Shimada; Masashi Mizuno; Takayuki Egusa; Munetaka Ohkouchi; Ikuya Shiromizu; Tomokazu Matsusue; Ichiro Yamamoto

doi:10.1016/j.bmcl.2006.02.064

Synthesis and evaluation of 4-substituted benzylamine derivatives as beta-tryptase inhibitors

Bioorg Med Chem Lett. 2006 Jun 1;16(11):2986-90. doi: 10.1016/j.bmcl.2006.02.064. Epub 2006 Mar 15.

Authors

Yutaka Miyazaki¹, Yutaka Kato, Tadashi Manabe, Hiroyasu Shimada, Masashi Mizuno, Takayuki Egusa, Munetaka Ohkouchi, Ikuya Shiromizu, Tomokazu Matsusue, Ichiro Yamamoto

Affiliation

¹ Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd, 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan. ymiya@mochida.co.jp

PMID: 16540315
DOI: 10.1016/j.bmcl.2006.02.064

Abstract

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.

MeSH terms

Benzylamines / chemical synthesis
Benzylamines / chemistry*
Benzylamines / pharmacology*
Ions / chemistry
Molecular Structure
Naphthalenes / chemistry
Serine Endopeptidases / metabolism*
Serine Proteinase Inhibitors / chemical synthesis*
Serine Proteinase Inhibitors / chemistry
Serine Proteinase Inhibitors / pharmacology*
Structure-Activity Relationship
Tryptases
Zinc / chemistry
Zinc / pharmacology

Substances

Benzylamines
Ions
Naphthalenes
Serine Proteinase Inhibitors
naphthalene
benzylamine
Serine Endopeptidases
Tryptases
Zinc