Discovery of pyridone-containing imidazolines as potent and selective inhibitors of neuropeptide Y Y5 receptor.
A series of 2-pyridone-containing imidazoline derivatives was synthesized and evaluated as neuropeptide Y Y5 receptor antagonists. Optimization of the 2-pyridone structure on the 2-position of the imidazoline ring led to identification of 1-(difluoromethyl)-5-[(4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl]pyridin-2(1H)-one (7m). Compound 7m displayed statistically significant inhibition of food intake in an agonist-induced food intake model in SD rats and no adverse cardiovascular effects in anesthetized dogs. In addition, markedly higher brain penetrability and a lower plasma Occ90 value were observed in P-gp-deficient mdr1a (-/-) mice compared to mdr1a (+/+) mice after oral administration of 7m.
Ando
Makoto
M
Tsukuba Research Institute, Banyu Pharmaceutical Company, Ltd, Okubo, Tsukuba, Japan. andoumkt@gmail.com
Sato
Nagaaki
N
Nagase
Tsuyoshi
T
Nagai
Keita
K
Ishikawa
Shiho
S
Takahashi
Hirobumi
H
Ohtake
Norikazu
N
Ito
Junko
J
Hirayama
Mioko
M
Mitobe
Yuko
Y
Iwaasa
Hisashi
H
Gomori
Akira
A
Matsushita
Hiroko
H
Tadano
Kiyoshi
K
Fujino
Naoko
N
Tanaka
Sachiko
S
Ohe
Tomoyuki
T
Ishihara
Akane
A
Kanatani
Akio
A
Fukami
Takehiro
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D048288:Imidazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
C544487:1-(difluoromethyl)-5-((4S,5S)-4-(4-fluorophenyl)-4-(6-fluoropyridin-3-yl)-5-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2(1H)-one; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019440:Anti-Obesity Agents; D048288:Imidazolines; D011728:Pyridones; D017476:Receptors, Neuropeptide Y; C100568:neuropeptide Y5 receptor