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 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.
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., Okubo 3, Tsukuba 300-2611, Japan.
Tsuyoshi
T
Nagase
Takashi
T
Mizutani
Etsuko
E
Sekino
Shiho
S
Ishikawa
Sayaka
S
Ito
Yuko
Y
Mitobe
Yasuhisa
Y
Miyamoto
Ryo
R
Yoshimoto
Takeshi
T
Tanaka
Akane
A
Ishihara
Norihiro
N
Takenaga
Shigeru
S
Tokita
Nagaaki
N
Sato
D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D017442:Histamine Agonists; D052999:Quinazolinones; D006632:Histamine