Synthesis and Evaluation of Structurally Constrained Quinazolinone Derivatives as Potent and Selective Histamine H3 Receptor Inverse Agonists

A series of structurally constrained derivatives of the potent H3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H3 receptor inverse agonists. As a result, the N-cyclobutylpiperidin-4-yloxy group as in 2f was identified as an optimal surrogate structure for the flexible 1-py...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2008-11, Vol.51 (21), p.6889-6901
Main Authors: Nagase, Tsuyoshi, Mizutani, Takashi, Sekino, Etsuko, Ishikawa, Shiho, Ito, Sayaka, Mitobe, Yuko, Miyamoto, Yasuhisa, Yoshimoto, Ryo, Tanaka, Takeshi, Ishihara, Akane, Takenaga, Norihiro, Tokita, Shigeru, Sato, Nagaaki
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood-Brain Barrier - metabolism
Brain - drug effects
Brain - metabolism
Brain - secretion
Histamine - metabolism
Histamine Agonists - chemical synthesis
Histamine Agonists - chemistry
Histamine Agonists - metabolism
Histamine Agonists - pharmacology
Humans
Medical sciences
Miscellaneous
Molecular Structure
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pharmacology. Drug treatments
Quinazolinones - chemical synthesis
Quinazolinones - chemistry
Quinazolinones - metabolism
Quinazolinones - pharmacology
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Summary:A series of structurally constrained derivatives of the potent H3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H3 receptor inverse agonists. As a result, the N-cyclobutylpiperidin-4-yloxy group as in 2f was identified as an optimal surrogate structure for the flexible 1-pyrrolidinopropoxy group of 1. Subsequent optimization of the quinazolinone core of 2f revealed that substitution at the 5-position of the quinazolinone ring influences potency. Representative derivatives 5a and 5s showed improved potency in a histamine release assay in rats and a receptor occupancy assay in mice.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm800569w