2HVX

Discovery of Potent, Orally Active, Nonpeptide Inhibitors of Human Mast Cell Chymase by Using Structure-Based Drug Design

2HVX の概要

• エントリーDOI: 10.2210/pdb2hvx/pdb
• 分子名称: Chymase, [(1S)-1-(5-CHLORO-1-BENZOTHIEN-3-YL)-2-(2-NAPHTHYLAMINO)-2-OXOETHYL]PHOSPHONIC ACID (3 entities in total)
• 機能のキーワード: serine protease, hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted: P23946
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 25423.69

構造登録者

Greco, M.N.,Hawkins, M.J.,Powell, E.T.,Almond, H.R.,de Garavilla, L.,Wang, Y.,Minor, L.A.,Wells, G.I.,Di Cera, E.,Cantwell, A.M.,Savvides, S.N.,Damiano, B.P.,Maryanoff, B.E. (登録日: 2006-07-31, 公開日: 2007-06-12, 最終更新日: 2024-10-30)

主引用文献

Greco, M.N.,Hawkins, M.J.,Powell, E.T.,Almond, H.R.,de Garavilla, L.,Hall, J.,Minor, L.K.,Wang, Y.,Corcoran, T.W.,Di Cera, E.,Cantwell, A.M.,Savvides, S.N.,Damiano, B.P.,Maryanoff, B.E.
Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
J.Med.Chem., 50:1727-1730, 2007

PubMed Abstract: A series of beta-carboxamido-phosphon(in)ic acids (2) was identified as a new structural motif for obtaining potent inhibitors of human mast cell chymase. For example, 1-naphthyl derivative 5f had an IC50 value of 29 nM and (E)-styryl derivative 6g had an IC50 value of 3.5 nM. An X-ray structure for 5f.chymase revealed key interactions within the enzyme active site. Compound 5f was selective for inhibiting chymase versus eight serine proteases. Compound 6h was orally bioavailable in rats (F=39%), and orally efficacious in a hamster model of inflammation.

PubMed: 17361995
DOI: 10.1021/jm0700619

実験手法

X-RAY DIFFRACTION (2.6 Å)