title: Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
abstract: By the screening of a combinatorial library for inhibitors of nitric oxide (NO) formation by the inducible isoform of nitric oxide synthase (iNOS) using a whole-cell assay, 2-(imidazol-1-yl)pyrimidines were identified. Compounds were found to inhibit the dimerization of iNOS monomers, thus preventing the formation of the dimeric, active form of the enzyme. Optimization led to the selection of the potent, selective, and orally available iNOS dimerization inhibitor, 21b, which significantly ameliorated adjuvant-induced arthritis in a rat model. Analysis of the crystal structure of the 21b--iNOS monomer complex provided a rationalization for both the SAR and the mechanism by which 21b blocks the formation of the protein--protein interaction present in the dimeric form of iNOS.
authors.affiliation: Berlex Biosciences, 2600 Hilltop Drive, P.O. Box 4099, Richmond, California 94804-0099, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Davey
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Damian
authors.initials: D
authors.lastname: Arnaiz
authors.forename: Keith
authors.initials: K
authors.lastname: Eagen
authors.forename: Shawn
authors.initials: S
authors.lastname: Erickson
authors.forename: William
authors.initials: W
authors.lastname: Guilford
authors.forename: Margaret
authors.initials: M
authors.lastname: Kenrick
authors.forename: Michael M
authors.initials: MM
authors.lastname: Morrissey
authors.forename: Mike
authors.initials: M
authors.lastname: Ohlmeyer
authors.forename: Gonghua
authors.initials: G
authors.lastname: Pan
authors.forename: Vidyadhar M
authors.initials: VM
authors.lastname: Paradkar
authors.forename: John
authors.initials: J
authors.lastname: Parkinson
authors.forename: Mark
authors.initials: M
authors.lastname: Polokoff
authors.forename: Kurt
authors.initials: K
authors.lastname: Saionz
authors.forename: Cecile
authors.initials: C
authors.lastname: Santos
authors.forename: Babu
authors.initials: B
authors.lastname: Subramanyam
authors.forename: Ron
authors.initials: R
authors.lastname: Vergona
authors.forename: Robert G
authors.initials: RG
authors.lastname: Wei
authors.forename: Marc
authors.initials: M
authors.lastname: Whitlow
authors.forename: Bin
authors.initials: B
authors.lastname: Ye
authors.forename: Zuchun Spring
authors.initials: ZS
authors.lastname: Zhao
authors.forename: James J
authors.initials: JJ
authors.lastname: Devlin
authors.forename: Gary
authors.initials: G
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000628:therapy; D052117:Benzodioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D019281:Dimerization; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008958:Models, Molecular; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052117:Benzodioxoles; D007093:Imidazoles; C519095:N-(2-(1,3-benzodioxol-5-yl)ethyl)-1-(2-(1H-imidazol-1-yl)-6-methyl-4-pyrimidinyl)-2-pyrrolidinecarboxamide; D011743:Pyrimidines; D052247:Nitric Oxide Synthase Type II