Reduction of CYP450 inhibition in the 4-[(1H-imidazol-4-yl)methyl]piperidine series of histamine H3 receptor antagonists

A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazol...

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Published in:Bioorganic & medicinal chemistry letters 2006-02, Vol.16 (4), p.989-994
Main Authors: BERLIN, Michael, TING, Pauline C, DUGUMA, Luli, SOLOMON, Daniel M, WEI ZHOU, SHER, Rosy, FAVREAU, Leonard, BRYANT, Matthew, KORFMACHER, Walter A, NARDO, Cymbelene, WEST, Robert E, ANTHES, John C, VACCARO, Wayne D, WILLIAMS, Shirley M, WU, Ren-Long, SHE, H. Susan, RIVELLI, Maria A, CORBOZ, Michel R, HEY, John A, ASLANIAN, Robert, MCCORMICK, Kevin D, LEE, Joe F, ALBANESE, Margaret M, MUTAHI, Mwangi W, PIWINSKI, John J, SHIH, Neng-Yang
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Guinea Pigs
Haplorhini
Histamine and antagonists. Allergy
Histamine Antagonists - chemical synthesis
Histamine Antagonists - chemistry
Histamine Antagonists - pharmacology
Humans
Imidazoles - chemical synthesis
Imidazoles - chemistry
Imidazoles - pharmacology
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Piperidines - chemical synthesis
Piperidines - chemistry
Piperidines - pharmacology
Rats
Receptors, Histamine H3 - drug effects
Structure-Activity Relationship
Tissue Distribution
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Summary:A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.10.087