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

被引：26

作者：

Uto, Yoshikazu ^{[1
]}

Ogata, Tsuneaki ^{[2
]}

Kiyotsuka, Yohei ^{[1
]}

Ueno, Yuko ^{[1
]}

Miyazawa, Yuriko ^{[1
]}

Kurata, Hitoshi ^{[1
]}

Deguchi, Tsuneo ^{[3
]}

Watanabe, Nobuaki ^{[3
]}

Konishi, Masahiro ^{[4
]}

Okuyama, Ryo ^{[4
]}

Kurikawa, Nobuya ^{[4
]}

Takagi, Toshiyuki ^{[5
]}

Wakimoto, Satoko ^{[4
]}

Ohsumi, Jun ^{[4
]}

机构：

[1] Daiichi Sankyo Co Ltd, Med Chem Res Labs 1, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Global Project Management Dept, Shinagawa Ku, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Biol Res Labs 2, Shinagawa Ku, Tokyo 1408710, Japan

[5] Daiichi Sankyo Co Ltd, Clin Dev Dept 1, Shinagawa Ku, Tokyo 1408710, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 01期

关键词：

Stearoyl-CoA desaturase (SCD); Benzoylpiperidine; Zucker fatty rat; POTENT INHIBITORS; SCD INHIBITORS; DISCOVERY; LEPTIN; GENE; MICE; DISRUPTION; OBESITY; TARGET; ESTERS;

D O I：

10.1016/j.bmcl.2009.10.101

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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). (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：341 / 345

页数：5

共 31 条

[1] Bromine-magnesium-exchange as a general tool for the preparation of polyfunctional aryl and heteroaryl magnesium-reagents [J].

Abarbri, M ;

Dehmel, F ;

Knochel, P .

TETRAHEDRON LETTERS, 1999, 40 (42) :7449-7453

[2]

ABREO M, 2005, Patent No. 2005011655

[3] ATHEROGENESIS IN 2 STRAINS OF OBESE RATS - THE FATTY ZUCKER AND LA/N-CORPULENT [J].

AMY, RM ;

DOLPHIN, PJ ;

PEDERSON, RA ;

RUSSELL, JC .

ATHEROSCLEROSIS, 1988, 69 (2-3) :199-209

[4] Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia [J].

Attie, AD ;

Krauss, RM ;

Gray-Keller, MP ;

Brownlie, A ;

Miyazaki, M ;

Kastelein, JJ ;

Lusis, AJ ;

Stalenhoef, AFH ;

Stoehr, JP ;

Hayden, MR ;

Ntambi, JM .

JOURNAL OF LIPID RESEARCH, 2002, 43 (11) :1899-1907

[5]

BLACK C, 2007, Patent No. 2007009236

[6] Phenotype of fatty due to Gln269Pro mutation in the leptin receptor (Lepr) [J].

Chua, SC ;

White, DW ;

WuPeng, XS ;

Liu, SM ;

Okada, N ;

Kershaw, EE ;

Chung, WK ;

PowerKehoe, L ;

Chua, M ;

Tartaglia, LA ;

Leibel, RL .

DIABETES, 1996, 45 (08) :1141-1143

[7] Stearoyl-CoA desaturase as a new drug target for obesity treatment [J].

Dobrzyn, A ;

Ntambi, JM .

OBESITY REVIEWS, 2005, 6 (02) :169-174

[8] Inhibition of stearoyl-CoA desaturase by cyclic amine derivatives [J].

Dobrzyn, Agnieszka ;

Dobrzyn, Pawel .

EXPERT OPINION ON THERAPEUTIC PATENTS, 2008, 18 (04) :457-460

[9] Stearoyl-CoA desaturase: A new therapeutic target of liver steatosis [J].

Dobrzyn, Pawel ;

Dobrzyn, Agnieszka .

DRUG DEVELOPMENT RESEARCH, 2006, 67 (08) :643-650

[10] Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism [J].

Flowers, Matthew T. ;

Ntambi, James M. .

CURRENT OPINION IN LIPIDOLOGY, 2008, 19 (03) :248-256

← 1 2 3 4 →