Design and synthesis of tricyclic compounds with enone functionalities in rings A and C: a novel class of highly active inhibitors of nitric oxide production in mouse macrophages.
Novel tricyclic compounds with enone functionalities in rings A and C, which were designed on the basis of the structure of a synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid, have been synthesized. Among them, 10 shows high inhibitory activity (IC(50) = 1 nM level) against production of nitric oxide induced by interferon-gamma in mouse macrophages and is orally active at 15 mg/kg (once) in a preliminary in vivo study using mouse peritoneal inflammation induced by thioglycollate and interferon-gamma.
Favaloro
Frank G
FG
Department of Chemistry, 6128 Burke Laboratory, Dartmouth College, Hanover, New Hampshire 03755, USA.
Honda
Tadashi
T
Honda
Yukiko
Y
Gribble
Gordon W
GW
Suh
Nanjoo
N
Risingsong
Renee
R
Sporn
Michael B
MB
D000818:Animals; D066298:In Vitro Techniques; D007371:Interferon-gamma; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010538:Peritonitis / Q000139:chemically induced / Q000188:drug therapy; D010616:Phenanthrenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013864:Thioglycolates; D014315:Triterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C467714:3,9-dicyano-5,6,6a,10a-tetrahydro-4a,7,7,10a-tetramethyl-2H-phenanthrene-2(4aH),8(7H)-dione; D009570:Nitriles; D010616:Phenanthrenes; D013864:Thioglycolates; D014315:Triterpenes; D009569:Nitric Oxide; D007371:Interferon-gamma