title: Discovery of potent, selective, orally active, nonpeptide inhibitors of human mast cell chymase.
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.
authors.affiliation: Research and Early Development, Johnson & Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19477-0776, USA. mgreco@prdus.jnj.com
authors.forename: Michael N
authors.initials: MN
authors.lastname: Greco
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hawkins
authors.forename: Eugene T
authors.initials: ET
authors.lastname: Powell
authors.forename: Harold R
authors.initials: HR
authors.lastname: Almond
authors.forename: Lawrence
authors.initials: L
authors.lastname: de Garavilla
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hall
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Minor
authors.forename: Yuanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Corcoran
authors.forename: Enrico
authors.initials: E
authors.lastname: Di Cera
authors.forename: Angelene M
authors.initials: AM
authors.lastname: Cantwell
authors.forename: Savvas N
authors.initials: SN
authors.lastname: Savvides
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: 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
chemical_list: 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