Lead optimization of 4-(dimethylamino)quinazolines, potent and selective antagonists for the melanin-concentrating hormone receptor 1.
Kanuma K,
Omodera K,
Nishiguchi M,
Funakoshi T,
Chaki S,
Semple G,
Tran TA,
Kramer B,
Hsu D,
Casper M,
Thomsen B,
Sekiguchi Y.
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan.
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 (IC50 = 3.4 nM) as well as good selectivity over the Y5 and the alpha2A receptors.
PMID: 16002290 [PubMed - indexed for MEDLINE]