Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
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.
Greco
Michael N
MN
Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, USA. mgreco@prdus.jnj.com
Hawkins
Michael J
MJ
Powell
Eugene T
ET
Almond
Harold R
HR
de Garavilla
Lawrence
L
Hall
Jeffrey
J
Minor
Lisa K
LK
Wang
Yuanping
Y
Corcoran
Thomas W
TW
Di Cera
Enrico
E
Cantwell
Angelene M
AM
Savvides
Savvas N
SN
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors; D053818:Chymases / Q000037:antagonists & inhibitors*; D006224:Cricetinae; D018360:Crystallography, X-Ray; D006801:Humans; D008407:Mast Cells / Q000201:enzymology*; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009281:Naphthalenes; D063065:Organophosphonates; D010721:Phosphinic Acids; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D053818:Chymases