Non-aromatic A-ring replacement in the triaryl bis-sulfone CB2 receptor inhibitors

A-ring replacements of 1 were investigated leading to compound 53 which had good affinity for the human CB2 receptor, reduced affinity for the rat calcium channel, and an improved cytochrome P450 profile. The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-01, Vol.20 (2), p.608-611
Main Authors: Gilbert, Eric J., Zhou, Guowei, Wong, Michael K.C., Tong, Ling, Shankar, Bandarpalle B., Huang, Chunli, Kelly, Joseph, Lavey, Brian J., McCombie, Stuart W., Chen, Lei, Rizvi, Razia, Dong, Youhao, Shu, Youheng, Kozlowski, Joseph A., Shih, Neng-Yang, Hipkin, R. William, Gonsiorek, Waldemar, Malikzay, Asra, Lunn, Charles A., Favreau, Len, Lundell, Daniel J.
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Calcium Channels - metabolism
Cannabinoid
CB2
Cytochrome P-450 Enzyme System
Drug Inverse Agonism
Humans
Inverse agonist
Medical sciences
Miscellaneous
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Piperidines - chemistry
Rats
Receptor, Cannabinoid, CB2 - antagonists & inhibitors
Receptor, Cannabinoid, CB2 - metabolism
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfones - chemical synthesis
Sulfones - chemistry
Sulfones - pharmacokinetics
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Summary:A-ring replacements of 1 were investigated leading to compound 53 which had good affinity for the human CB2 receptor, reduced affinity for the rat calcium channel, and an improved cytochrome P450 profile. The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2009.11.084