Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
J Med Chem
; 50(8): 1727-30, 2007 Apr 19.
Article
em En
| MEDLINE
| ID: mdl-17361995
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.
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Base de dados:
MEDLINE
Assunto principal:
Ácidos Fosfínicos
/
Anti-Inflamatórios não Esteroides
/
Quimases
/
Organofosfonatos
/
Amidas
/
Mastócitos
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos