4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable stearoyl-CoA desaturase-1 (SCD1) inhibitors: Part 2. Pyridazine-based analogs

被引：6

作者：

Yang, Shyh-Ming ^{[1
]}

Tang, Yuting ^{[1
]}

Rano, Thomas ^{[1
]}

Lu, Huajun ^{[1
]}

Kuo, Gee-Hong ^{[1
]}

Gaul, Michael D. ^{[1
]}

Li, Yaxin ^{[1
]}

Ho, George ^{[1
]}

Lang, Wensheng ^{[1
]}

Conway, James G. ^{[1
]}

Liang, Yin ^{[1
]}

Lenhard, James M. ^{[1
]}

Demarest, Keith T. ^{[1
]}

Murray, William V. ^{[1
]}

机构：

[1] Janssen Res & Dev LLC, Cardiovasc & Metab Res, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 05期

关键词：

Stearoyl-CoA desaturase; SCD1; inhibitors; Desaturation index; obesity; LIVER; DISCOVERY; GENE; MICE; CHOLESTEROL; EFFICACY; SERIES; ACIDS;

D O I：

10.1016/j.bmcl.2013.12.075

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Design, synthesis, and biological evaluation of pyridazine-based, 4-bicyclic heteroaryl-piperidine derivatives as potent stearoyl-CoA desaturase-1 (SCD1) inhibitors are described. In a chronic study of selected analog (3e) in Zucker fa/fa (ZF) rat, dose-dependent decrease of body weight gain and plasma fatty acid desaturation index (DI) in both C16 and C18 are also demonstrated. The results indicate that the plasma fatty acid DI may serve as an indicator for direct target engagement and biomarker for SCD1 inhibition. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1437 / 1441

页数：5

共 10 条

[1] 4-Bicyclic heteroaryl-piperidine derivatives as potent, orally bioavailable Stearoyl-CoA desaturase-1 (SCD1) inhibitors. Part 1: Urea-based analogs
Yang, Shyh-Ming
Tang, Yuting
Zhang, Rui
Lu, Huajun
Kuo, Gee-Hong
Gaul, Michael D.
Li, Yaxin
Ho, George
Conway, James G.
Liang, Yin
Lenhard, James M.
Demarest, Keith T.
Murray, William V.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (24) : 6773 - 6776
[2] Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors
Sun, Shaoyi
Zhang, Zaihui
Pokrovskaia, Natalia
Chowdhury, Sultan
Jia, Qi
Chang, Elaine
Khakh, Kuldip
Kwan, Rainbow
McLaren, David G.
Radomski, Chris C.
Ratkay, Leslie G.
Fu, Jianmin
Dales, Natalie A.
Winther, Michael D.
BIOORGANIC & MEDICINAL CHEMISTRY, 2015, 23 (03) : 455 - 465
[3] Benzimidazole-carboxamides as potent and bioavailable stearoyl-CoA desaturase (SCD1) inhibitors from ligand-based virtual screening and chemical optimization
Matter, Hans
Zoller, Gerhard
Herling, Andreas W.
Sanchez-Arias, Juan-Antonio
Philippo, Christophe
Namane, Claudie
Kohlmann, Markus
Pfenninger, Anja
Voss, Marc D.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (06) : 1817 - 1822
[4] Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors, thiazole-4-acetic acid derivatives, for the treatment of diabetes, hepatic steatosis, and obesity
Iida, Tetsuya
Ubukata, Minoru
Mitani, Ikuo
Nakagawa, Yuichi
Maeda, Katsuya
Imai, Hiroto
Ogoshi, Yosuke
Hotta, Takahiro
Sakata, Shohei
Sano, Ryuhei
Morinaga, Hisayo
Negoro, Tamotsu
Oshida, Shinichi
Tanaka, Masahiro
Inaba, Takashi
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2018, 158 : 832 - 852
[5] Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic Syndrome
Zhang, Zaihui
Sun, Shaoyi
Kodumuru, Vishnumurthy
Hou, Duanjie
Liu, Shifeng
Chakka, Nagasree
Sviridov, Serguei
Chowdhury, Sultan
McLaren, David G.
Ratkay, Leslie G.
Khakh, Kuldip
Cheng, Xing
Gschwend, Heinz W.
Kamboj, Rajender
Fu, Jianmin
Winther, Michael D.
JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (02) : 568 - 583
[6] Synthesis and evaluation of novel stearoyl-CoA desaturase 1 inhibitors: 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4′-piperidine] analogs
Uto, Yoshikazu
Ueno, Yuko
Kiyotsuka, Yohei
Miyazawa, Yuriko
Kurata, Hitoshi
Ogata, Tsuneaki
Yamada, Makiko
Deguchi, Tsuneo
Konishi, Masahiro
Takagi, Toshiyuki
Wakimoto, Satoko
Ohsumi, Jun
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2010, 45 (11) : 4788 - 4796
[7] Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part II: Identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide and its biological evaluation
Uto, Yoshikazu
Ogata, Tsuneaki
Kiyotsuka, Yohei
Miyazawa, Yuriko
Ueno, Yuko
Kurata, Hitoshi
Deguchi, Tsuneo
Yamada, Makiko
Watanabe, Nobuaki
Takagi, Toshiyuki
Wakimoto, Satoko
Okuyama, Ryo
Konishi, Masahiro
Kurikawa, Nobuya
Kono, Keita
Osumi, Jun
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (15) : 4159 - 4166
[8] 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
Uto, Yoshikazu
Ogata, Tsuneaki
Kiyotsuka, Yohei
Ueno, Yuko
Miyazawa, Yuriko
Kurata, Hitoshi
Deguchi, Tsuneo
Watanabe, Nobuaki
Konishi, Masahiro
Okuyama, Ryo
Kurikawa, Nobuya
Takagi, Toshiyuki
Wakimoto, Satoko
Ohsumi, Jun
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (01) : 341 - 345
[9] Novel and potent inhibitors of stearoyl-CoA desaturase-1. Part I: Discovery of 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide
Uto, Yoshikazu
Ogata, Tsuneaki
Harada, Jun
Kiyotsuka, Yohei
Ueno, Yuko
Miyazawa, Yuriko
Kurata, Hitoshi
Deguchi, Tsuneo
Watanabe, Nobuaki
Takagi, Toshiyuki
Wakimoto, Satoko
Okuyama, Ryo
Abe, Manabu
Kurikawa, Nobuya
Kawamura, Sayako
Yamato, Michiko
Osumi, Jun
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (15) : 4151 - 4158
[10] Novel spiropiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 1′-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4′-piperidine]
Uto, Yoshikazu
Kiyotsuka, Yohei
Ueno, Yuko
Miyazawa, Yuriko
Kurata, Hitoshi
Ogata, Tsuneaki
Deguchi, Tsuneo
Yamada, Makiko
Watanabe, Nobuaki
Konishi, Masahiro
Kurikawa, Nobuya
Takagi, Toshiyuki
Wakimoto, Satoko
Kono, Keita
Ohsumi, Jun
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (02) : 746 - 754

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