Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1

• Published in: Bioorganic & medicinal chemistry letters Vol. 15; no. 17; pp. 3853 - 3856
• Main Authors: Kanuma, Kosuke, Omodera, Katsunori, Nishiguchi, Mariko, Funakoshi, Takeo, Chaki, Shigeyuki, Semple, Graeme, Tran, Thuy-Anh, Kramer, Bryan, Hsu, Debbie, Casper, Martin, Thomsen, Bill, Sekiguchi, Yoshinori
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01-09-2005; Elsevier
• Subjects: ATC0175; Biological and medical sciences; Hormones. Endocrine system; Humans; Inhibitory Concentration 50; MCH-R1 antagonists; Medical sciences; Melanin-concentrating hormone receptor 1 antagonists; Pharmacology. Drug treatments; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Radioligand Assay; Receptors, Somatostatin - antagonists & inhibitors; Structure-Activity Relationship; Substrate Specificity; Melanin-concentrating hormone receptor 1 antagonists; MCH-R1 antagonists; ATC0175; Cyclohexane derivatives; Spacer arm; Quinazoline derivatives; Selectivity; Optimization; Structure activity relation; Hydrochlorides; Organic fluorine compounds; Melanin concentrating hormone; Benzamide derivatives; Carboxamide; Antagonist; Chemical synthesis; Biological receptor; Hormonal receptor
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2005.05.121

The synthesis and SAR of 4-(dimethylamino)quinazolines as melanin-concentrating hormone receptor 1 (MCH-R1) antagonists are reported, leading to the discovery of ATC0175.
The optimization of a series of 4-(dimethylamino)quinazoline antagonists of the melanin-concentrating hormone receptor 1 (MCH-R1) is described. The combination of the elaboration of both the linker portion and the terminal phenyl ring provided
N-(
cis-4-{[4-(dimethylamino)quinazolin-2-yl]amino}cyclohexyl)-3,4-difluorobenzamide hydrochloride
28 (ATC0175), which showed excellent antagonist activity at the MCH-R1 (IC
50
=
3.4
nM) as well as good selectivity over the Y5 and the α
2A receptors.