Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties

Stephen T Wrobleski; Ping Chen; John Hynes Jr; Shuqun Lin; Derek J Norris; Chennagiri R Pandit; Steven Spergel; Hong Wu; John S Tokarski; Xiaorong Chen; Kathleen M Gillooly; Peter A Kiener; Kim W McIntyre; Vina Patil-Koota; David J Shuster; Lori A Turk; Guchen Yang; Katerina Leftheris

doi:10.1021/jm020329q

Rational design and synthesis of an orally active indolopyridone as a novel conformationally constrained cannabinoid ligand possessing antiinflammatory properties

J Med Chem. 2003 May 22;46(11):2110-6. doi: 10.1021/jm020329q.

Authors

Stephen T Wrobleski¹, Ping Chen, John Hynes Jr, Shuqun Lin, Derek J Norris, Chennagiri R Pandit, Steven Spergel, Hong Wu, John S Tokarski, Xiaorong Chen, Kathleen M Gillooly, Peter A Kiener, Kim W McIntyre, Vina Patil-Koota, David J Shuster, Lori A Turk, Guchen Yang, Katerina Leftheris

Affiliation

¹ Department of Discovery Chemistry, Bristol-Myers Squibb, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA. [email protected]

PMID: 12747783
DOI: 10.1021/jm020329q

Abstract

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.

MeSH terms

Administration, Oral
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology
Cannabinoids / metabolism*
Cells, Cultured
Cricetinae
Drug Design
Female
Humans
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacology
Inflammation / chemically induced
Inflammation / metabolism
Leukocytes, Mononuclear / metabolism
Ligands
Lipopolysaccharides
Mice
Mice, Inbred BALB C
Models, Molecular
Molecular Conformation
Norbornanes / chemical synthesis*
Norbornanes / chemistry
Norbornanes / pharmacology
Pyridones / chemical synthesis*
Pyridones / chemistry
Pyridones / pharmacology
Receptors, Cannabinoid
Receptors, Drug / agonists*
Structure-Activity Relationship
Tumor Necrosis Factor-alpha / metabolism

Substances

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
Anti-Inflammatory Agents, Non-Steroidal
Cannabinoids
Indoles
Ligands
Lipopolysaccharides
Norbornanes
Pyridones
Receptors, Cannabinoid
Receptors, Drug
Tumor Necrosis Factor-alpha