Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats.
Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd).
Uto
Yoshikazu
Y
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co. Ltd, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. uto.yoshikazu.pw@daiichisankyo.co.jp
Ogata
Tsuneaki
T
Kiyotsuka
Yohei
Y
Ueno
Yuko
Y
Miyazawa
Yuriko
Y
Kurata
Hitoshi
H
Deguchi
Tsuneo
T
Watanabe
Nobuaki
N
Konishi
Masahiro
M
Okuyama
Ryo
R
Kurikawa
Nobuya
N
Takagi
Toshiyuki
T
Wakimoto
Satoko
S
Ohsumi
Jun
J
D000284:Administration, Oral; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
C549137:6-(4-(2-methylbenzoyl)piperidin-1-yl)pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010880:Piperidines; D011724:Pyridazines; D011725:Pyridines; D014280:Triglycerides; D013230:Stearoyl-CoA Desaturase