Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

Takashi Mizutani; Tsuyoshi Nagase; Sayaka Ito; Yasuhisa Miyamoto; Takeshi Tanaka; Norihiro Takenaga; Shigeru Tokita; Nagaaki Sato

doi:10.1016/j.bmcl.2008.10.034

Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

Bioorg Med Chem Lett. 2008 Dec 1;18(23):6041-5. doi: 10.1016/j.bmcl.2008.10.034. Epub 2008 Oct 11.

Authors

Takashi Mizutani¹, Tsuyoshi Nagase, Sayaka Ito, Yasuhisa Miyamoto, Takeshi Tanaka, Norihiro Takenaga, Shigeru Tokita, Nagaaki Sato

Affiliation

¹ Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.

PMID: 18952421
DOI: 10.1016/j.bmcl.2008.10.034

Abstract

Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study.

MeSH terms

Administration, Oral
Adrenergic alpha-1 Receptor Antagonists*
Brain / drug effects
Combinatorial Chemistry Techniques
Dose-Response Relationship, Drug
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
Histamine Agonists / pharmacology*
Humans
Molecular Structure
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Adrenergic alpha-1 Receptor Antagonists
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels
Histamine Agonists
KCNH2 protein, human
Quinazolinones