Discovery of pyrrolopyridazines as novel DGAT1 inhibitors

被引：27
|
作者：
Fox, Brian M. [1 ]
Iio, Kiyosei [2 ]
Li, Kexue [1 ]
Choi, Rebeka [1 ]
Inaba, Takashi [2 ]
Jackson, Simon [1 ]
Sagawa, Shoichi [2 ]
Shan, Bei [1 ]
Tanaka, Masahiro [2 ]
Yoshida, Atsuhito [2 ]
Kayser, Frank [1 ]
机构：
[1] Amgen Inc, Amgen S San Francisco, San Francisco, CA 94080 USA
[2] Japan Tobacco Inc, Cent Pharmaceut Res Inst, Osaka 5691125, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 20期
关键词：
DGAT1; inhibitors; Pyrrolopyridazines; Acyl CoA: diacylglycerol acyltransferase; COA-DIACYLGLYCEROL ACYLTRANSFERASE; TRIGLYCERIDE SYNTHESIS; OBESITY; CLONING; RESISTANCE; INSULIN; FAMILY; TARGET;
D O I：
10.1016/j.bmcl.2010.08.066
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 mu M to 48 nM. (c) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码：6030 / 6033
页数：4
相关论文
共 50 条
  • [21] Deconstructing the DGAT1 Enzyme: Membrane Interactions at Substrate Binding Sites
    Lopes, Jose L. S.
    Beltramini, Leila M.
    Wallace, Bonnie A.
    Araujo, Ana P. U.
    PLOS ONE, 2015, 10 (02):
  • [22] Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety
    He, Shuwen
    Hong, Qingmei
    Lai, Zhong
    Wu, Zhicai
    Yu, Yang
    Kim, David W.
    Ting, Pauline C.
    Kuethe, Jeffrey T.
    Yang, Ginger X.
    Jian, Tianying
    Liu, Jian
    Guiadeen, Deodial
    Krikorian, Arto D.
    Sperbeck, Donald M.
    Sonatore, Lisa M.
    Wiltsie, Judyann
    Chung, Christine C.
    Gibson, Jack T.
    Lisnock, JeanMarie
    Murphy, Beth A.
    Gorski, Judith N.
    Liu, Jinqi
    Chen, Dunlu
    Chen, Xiaoli
    Wolff, Michael
    Tong, Sharon X.
    Madeira, Maria
    Karanam, Bindhu V.
    Shen, Dong-Ming
    Balkovec, James M.
    Pinto, Shiny
    Nargund, Ravi P.
    DeVita, Robert J.
    ACS MEDICINAL CHEMISTRY LETTERS, 2013, 4 (08): : 773 - 778
  • [23] Discovery of 6-Phenylpyrimido[4,5-b][1,4]oxazines as Potent and Selective Acyl CoA:Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors with in Vivo Efficacy in Rodents
    Fox, Brian M.
    Sugimoto, Kazuyuki
    Iio, Kiyosei
    Yoshida, Atsuhito
    Zhang, Jian
    Li, Kexue
    Hao, Xiaolin
    Labelle, Marc
    Smith, Marie-Louise
    Rubenstein, Steven M.
    Ye, Guosen
    McMinn, Dustin
    Jackson, Simon
    Choi, Rebekah
    Shan, Bei
    Ma, Ji
    Miao, Shichang
    Matsui, Takuya
    Ogawa, Nobuya
    Suzuki, Masahiro
    Kobayashi, Akio
    Ozeki, Hidekazu
    Okuma, Chihiro
    Ishii, Yukihito
    Tomimoto, Daisuke
    Furakawa, Noboru
    Tanaka, Masahiro
    Matsushita, Mutsuyoshi
    Takahashi, Mitsuru
    Inaba, Takashi
    Sagawa, Shoichi
    Kayser, Frank
    JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (08) : 3464 - 3483
  • [24] Cloning and characterization of DGAT1 gene of Riverine buffalo
    Venkatachalapathy, R. T.
    Sharma, Arjava
    Sukla, Soumi
    Hattacharya, Tarun K.
    DNA SEQUENCE, 2008, 19 (03): : 177 - 184
  • [25] Identification of 2-aminooxazole amides as acyl-CoA: Diacylglycerol acyltransferase 1 (DGAT1) inhibitors through scaffold hopping strategy
    Kim, Hyunjin M.
    Smith, Michelle D.
    Kim, Jae-Hun
    Caplen, Mary Ann
    Chan, Tin Yau
    McKittrick, Brian A.
    Cook, John A.
    Van Heek, Margaret
    Lachowicz, Jean
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (23) : 6410 - 6414
  • [26] Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally bioavailable DGAT1 inhibitors that suppress body weight in diet-induced mouse obesity model
    Yu, Tao
    Wu, Chengde
    Shih, NengYang
    Li, Qi
    Chan, Chichung
    Pan, He
    Yao, Dan
    Pan, Yan
    Liang, Wei
    Shen, Liang
    Zhao, Hui
    Li, Jian
    Chen, Shuhui
    BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2018, 28 (10) : 1686 - 1692
  • [27] Synthesis and biological evaluation of isoxazole, oxazole, and oxadiazole containing heteroaryl analogs of biaryl ureas as DGAT1 inhibitors
    Jadhav, Ravindra D.
    Kadam, Kishorkumar S.
    Kandre, Shivaji
    Guha, Tandra
    Reddy, M. Mahesh Kumar
    Brahma, Manoja K.
    Deshmukh, Nitin J.
    Dixit, Amol
    Doshi, Lalit
    Potdar, Nisha
    Enose, Arno A.
    Vishwakarma, Ram A.
    Sivaramakrishnan, H.
    Srinivasan, Shaila
    Nemmani, Kumar V. S.
    Gupte, Amol
    Gangopadhyay, Ashok K.
    Sharma, Rajiv
    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2012, 54 : 324 - 342
  • [28] Characterisation of DGAT1 and DGAT2 from Jatropha curcas and their functions in storage lipid biosynthesis
    Xu, Ronghua
    Yang, Tianquan
    Wang, Ruling
    Liu, Aizhong
    FUNCTIONAL PLANT BIOLOGY, 2014, 41 (03) : 321 - 329
  • [29] Targeting Acyl-CoA:Diacylglycerol Acyltransferase 1 (DGAT1) with Small Molecule Inhibitors for the Treatment of Metabolic Diseases
    Cao, Jingsong
    Zhou, Yingjiang
    Peng, Haibing
    Huang, Xinyi
    Stahler, Shannon
    Suri, Vipin
    Qadri, Ariful
    Gareski, Tiffany
    Jones, Juli
    Hahm, Seung
    Perreault, Mylene
    McKew, John
    Shi, Mengxiao
    Xu, Xin
    Tobin, James F.
    Gimeno, Ruth E.
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (48) : 41838 - 41851
  • [30] LQTA-R: A new 3D-QSAR methodology applied to a set of DGAT1 inhibitors
    Patil, Rajesh B.
    Barbosa, Euzebio G.
    Sangshetti, Jaiprakash N.
    Sawant, Sanjay D.
    Zambre, Vishal P.
    COMPUTATIONAL BIOLOGY AND CHEMISTRY, 2018, 74 : 123 - 131
12345