Design, synthesis, and activity of 2-imidazol-1-ylpyrimidine derived inducible nitric oxide synthase dimerization inhibitors.
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.
Davey
David D
DD
Berlex Biosciences, 2600 Hilltop Drive, P.O. Box 4099, Richmond, California 94804-0099, USA.
Adler
Marc
M
Arnaiz
Damian
D
Eagen
Keith
K
Erickson
Shawn
S
Guilford
William
W
Kenrick
Margaret
M
Morrissey
Michael M
MM
Ohlmeyer
Mike
M
Pan
Gonghua
G
Paradkar
Vidyadhar M
VM
Parkinson
John
J
Polokoff
Mark
M
Saionz
Kurt
K
Santos
Cecile
C
Subramanyam
Babu
B
Vergona
Ron
R
Wei
Robert G
RG
Whitlow
Marc
M
Ye
Bin
B
Zhao
Zuchun Spring
ZS
Devlin
James J
JJ
Phillips
Gary
G
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
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