2HVX

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

Summary for 2HVX

• Entry DOI: 10.2210/pdb2hvx/pdb
• Descriptor: Chymase, [(1S)-1-(5-CHLORO-1-BENZOTHIEN-3-YL)-2-(2-NAPHTHYLAMINO)-2-OXOETHYL]PHOSPHONIC ACID (3 entities in total)
• Functional Keywords: serine protease, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P23946
• Total number of polymer chains: 1
• Total formula weight: 25423.69

Authors

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. (deposition date: 2006-07-31, release date: 2007-06-12, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.6 Å)