Synthesis and evaluation of structurally constrained quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

  • J Med Chem. 2008 Nov 13;51(21):6889-901. doi: 10.1021/jm800569w.
Tsuyoshi Nagase  1 ,  Takashi Mizutani ,  Etsuko Sekino ,  Shiho Ishikawa ,  Sayaka Ito ,  Yuko Mitobe ,  Yasuhisa Miyamoto ,  Ryo Yoshimoto ,  Takeshi Tanaka ,  Akane Ishihara ,  Norihiro Takenaga ,  Shigeru Tokita ,  Nagaaki Sato
Affiliations
  • 1. Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan.
PMID: 18841880 DOI: 10.1021/jm800569w
Abstract

A series of structurally constrained derivatives of the potent H 3 inverse agonist 1 was designed, synthesized, and evaluated as histamine H 3 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.

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