2. Academic Validation
  3. Synthesis and evaluation of structurally constrained quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

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

Affiliation

  • 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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