Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties.
A series of unique indazoles and pyridoindolones have been rationally designed and synthesized as novel classes of cannabinoid ligands based on a proposed bioactive amide conformation. This has led to the discovery of the novel indolopyridone 3a as a conformationally constrained cannabinoid ligand that displays high affinity for the CB2 receptor (K(i)(CB2) = 1.0 nM) and possesses antiinflammatory properties when administered orally in an in vivo murine inflammation model.
Department of Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. stephen.wrobleski@bms.com
Stephen T
ST
Wrobleski
Ping
P
Chen
John
J
Hynes
Shuqun
S
Lin
Derek J
DJ
Norris
Chennagiri R
CR
Pandit
Steven
S
Spergel
Hong
H
Wu
John S
JS
Tokarski
Xiaorong
X
Chen
Kathleen M
KM
Gillooly
Peter A
PA
Kiener
Kim W
KW
McIntyre
Vina
V
Patil-Koota
David J
DJ
Shuster
Lori A
LA
Turk
Guchen
G
Yang
Katerina
K
Leftheris
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002186:Cannabinoids / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D015195:Drug Design; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008024:Ligands; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D008968:Molecular Conformation; D009636:Norbornanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C474820:2,5-dihydro-6-methoxy-5-(2-(4-morpholinyl)ethyl)-2-(1,3,3-trimethylbicyclo(2.2.1)heptan-2-yl)-1H-pyrido(4,3-b)indol-1-one; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002186:Cannabinoids; D007211:Indoles; D008024:Ligands; D008070:Lipopolysaccharides; D009636:Norbornanes; D011728:Pyridones; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D014409:Tumor Necrosis Factor-alpha