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.
MeSH terms
-
Administration, Oral
-
Amides / chemical synthesis*
-
Amides / chemistry
-
Amides / pharmacology
-
Animals
-
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
-
Anti-Inflammatory Agents, Non-Steroidal / chemistry
-
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
-
Binding Sites
-
Biological Availability
-
Cathepsin G
-
Cathepsins / antagonists & inhibitors
-
Chymases / antagonists & inhibitors*
-
Cricetinae
-
Crystallography, X-Ray
-
Humans
-
Mast Cells / enzymology*
-
Models, Molecular
-
Naphthalenes / chemical synthesis
-
Naphthalenes / chemistry
-
Naphthalenes / pharmacology
-
Organophosphonates / chemical synthesis*
-
Organophosphonates / chemistry
-
Organophosphonates / pharmacology
-
Phosphinic Acids / chemical synthesis*
-
Phosphinic Acids / chemistry
-
Phosphinic Acids / pharmacology
-
Rats
-
Serine Endopeptidases
-
Stereoisomerism
-
Structure-Activity Relationship
Substances
-
Amides
-
Anti-Inflammatory Agents, Non-Steroidal
-
Naphthalenes
-
Organophosphonates
-
Phosphinic Acids
-
Cathepsins
-
Serine Endopeptidases
-
CTSG protein, human
-
Cathepsin G
-
Ctsg protein, rat
-
Chymases