Literature DB >> 24900485

Intestinally Targeted Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitors Robustly Suppress Postprandial Triglycerides.

Michael H Serrano-Wu1, Gary M Coppola1, Yongjin Gong1, Alan D Neubert1, Ricardo Chatelain1, Kevin B Clairmont1, Renee Commerford1, Theresa Cosker1, Thomas Daniels1, Ying Hou1, Monish Jain1, Marlene Juedes1, Lisha Li1, Tara Mullarkey1, Erik Rocheford1, Moo Je Sung1, Andrew Tyler1, Qing Yang1, Taeyoung Yoon1, Brian K Hubbard1.   

Abstract

High DGAT1 expression levels in the small intestine highlight the critical role this enzyme plays in nutrient absorption. Identification of inhibitors which predominantly inhibit DGAT1 in the gut is an attractive drug discovery strategy with anticipated benefits of reduced systemic toxicity. In this report we describe our discovery and optimization of DGAT1 inhibitors whose plasma exposure is minimized by the action of transporters, including the P-glycoprotein transporter. The impact of this unique absorption profile on efficacy in rat and dog efficacy models is presented.

Entities:  

Keywords:  DGAT1; efflux; triglyceride synthesis

Year:  2012        PMID： 24900485      PMCID： PMC4025815          DOI： 10.1021/ml3000512

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  17 in total

1.  Identification and preliminary characterization of a potent, safe, and orally efficacious inhibitor of acyl-CoA:diacylglycerol acyltransferase 1.

Authors:  Vince S C Yeh; David W A Beno; Sevan Brodjian; Michael E Brune; Steven C Cullen; Brian D Dayton; Madhup K Dhaon; Hugh D Falls; Ju Gao; Nelson Grihalde; Philip Hajduk; T Matthew Hansen; Andrew S Judd; Andrew J King; Russel C Klix; Kelly J Larson; Yau Y Lau; Kennan C Marsh; Scott W Mittelstadt; Dan Plata; Michael J Rozema; Jason A Segreti; Eric J Stoner; Martin J Voorbach; Xiaojun Wang; Xili Xin; Gang Zhao; Christine A Collins; Bryan F Cox; Regina M Reilly; Philip R Kym; Andrew J Souers
Journal:  J Med Chem       Date:  2012-02-10       Impact factor: 7.446

2.  Leptin modulates the effects of acyl CoA:diacylglycerol acyltransferase deficiency on murine fur and sebaceous glands.

Authors:  Hubert C Chen; Steven J Smith; Bryan Tow; Peter M Elias; Robert V Farese
Journal:  J Clin Invest       Date:  2002-01       Impact factor: 14.808

Review 3.  Transporter-mediated drug uptake and efflux: important determinants of adverse drug reactions.

Authors:  O Zolk; M F Fromm
Journal:  Clin Pharmacol Ther       Date:  2011-04-06       Impact factor: 6.875

Review 4.  DGAT1 inhibitors as anti-obesity and anti-diabetic agents.

Authors:  Alan M Birch; Linda K Buckett; Andrew V Turnbull
Journal:  Curr Opin Drug Discov Devel       Date:  2010-07

5.  Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat.

Authors:  S J Smith; S Cases; D R Jensen; H C Chen; E Sande; B Tow; D A Sanan; J Raber; R H Eckel; R V Farese
Journal:  Nat Genet       Date:  2000-05       Impact factor: 38.330

6.  Intestine-specific expression of acyl CoA:diacylglycerol acyltransferase 1 reverses resistance to diet-induced hepatic steatosis and obesity in Dgat1-/- mice.

Authors:  Bonggi Lee; Angela M Fast; Jiabin Zhu; Ji-Xin Cheng; Kimberly K Buhman
Journal:  J Lipid Res       Date:  2010-02-10       Impact factor: 5.922

7.  Characterization of acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) enzyme of human small intestine.

Authors:  Yasushi Hiramine; Toshizumi Tanabe
Journal:  J Physiol Biochem       Date:  2011-01-08       Impact factor: 4.158

8.  Cloning of DGAT2, a second mammalian diacylglycerol acyltransferase, and related family members.

Authors:  S Cases; S J Stone; P Zhou; E Yen; B Tow; K D Lardizabal; T Voelker; R V Farese
Journal:  J Biol Chem       Date:  2001-07-31       Impact factor: 5.157

9.  Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1.

Authors:  Hubert C Chen; Steven J Smith; Zuleika Ladha; Dalan R Jensen; Luis D Ferreira; Leslie K Pulawa; James G McGuire; Robert E Pitas; Robert H Eckel; Robert V Farese
Journal:  J Clin Invest       Date:  2002-04       Impact factor: 14.808

Review 10.  Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice.

Authors:  Hubert C Chen; Robert V Farese
Journal:  Arterioscler Thromb Vasc Biol       Date:  2004-11-29       Impact factor: 8.311
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  7 in total

1.  Discovery of a Potent and Selective DGAT1 Inhibitor with a Piperidinyl-oxy-cyclohexanecarboxylic Acid Moiety.

Authors:  Shuwen He; Qingmei Hong; Zhong Lai; David X Yang; Pauline C Ting; Jeffrey T Kuethe; Timothy A Cernak; Kevin D Dykstra; Donald M Sperbeck; Zhicai Wu; Yang Yu; Ginger X Yang; Tianying Jian; Jian Liu; Deodial Guiadeen; Arto D Krikorian; Lisa M Sonatore; Judyann Wiltsie; Jinqi Liu; Judith N Gorski; Christine C Chung; Jack T Gibson; JeanMarie Lisnock; Jianying Xiao; Michael Wolff; Sharon X Tong; Maria Madeira; Bindhu V Karanam; Dong-Ming Shen; James M Balkovec; Shirly Pinto; Ravi P Nargund; Robert J DeVita
Journal:  ACS Med Chem Lett       Date:  2014-09-08       Impact factor: 4.345

Review 2.  Amide Bond Bioisosteres: Strategies, Synthesis, and Successes.

Authors:  Shikha Kumari; Angelica V Carmona; Amit K Tiwari; Paul C Trippier
Journal:  J Med Chem       Date:  2020-08-04       Impact factor: 7.446

3.  Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety.

Authors:  Shuwen He; Qingmei Hong; Zhong Lai; Zhicai Wu; Yang Yu; David W Kim; Pauline C Ting; Jeffrey T Kuethe; Ginger X Yang; Tianying Jian; Jian Liu; Deodial Guiadeen; Arto D Krikorian; Donald M Sperbeck; Lisa M Sonatore; Judyann Wiltsie; Christine C Chung; Jack T Gibson; JeanMarie Lisnock; Beth A Murphy; Judith N Gorski; Jinqi Liu; Dunlu Chen; Xiaoli Chen; Michael Wolff; Sharon X Tong; Maria Madeira; Bindhu V Karanam; Dong-Ming Shen; James M Balkovec; Shirly Pinto; Ravi P Nargund; Robert J DeVita
Journal:  ACS Med Chem Lett       Date:  2013-06-06       Impact factor: 4.345

4.  Successful Strategies for Mitigation of a Preclinical Signal for Phototoxicity in a DGAT1 Inhibitor.

Authors:  Tyler J Harrison; Daniel Bauer; Alina Berdichevsky; Xin Chen; Rohit Duvadie; Benjamin Hoogheem; Panos Hatsis; Qian Liu; Justin Mao; Vasumathy Miduturu; Erik Rocheford; Frederic Zecri; Richard Zessis; Rui Zheng; Qingming Zhu; Ryan Streeper; Sejal J Patel
Journal:  ACS Med Chem Lett       Date:  2019-06-20       Impact factor: 4.345

5.  Design, Synthesis, and Biological Evaluation of a Novel Series of 4-Guanidinobenzoate Derivatives as Enteropeptidase Inhibitors with Low Systemic Exposure for the Treatment of Obesity.

Authors:  Zenichi Ikeda; Keiko Kakegawa; Fumiaki Kikuchi; Sachiko Itono; Hideyuki Oki; Hiroaki Yashiro; Hideyuki Hiyoshi; Kazue Tsuchimori; Kenichi Hamagami; Masanori Watanabe; Masako Sasaki; Youko Ishihara; Kimio Tohyama; Tomoyuki Kitazaki; Tsuyoshi Maekawa; Minoru Sasaki
Journal:  J Med Chem       Date:  2022-06-10       Impact factor: 8.039

6.  Intestine-targeted DGAT1 inhibition improves obesity and insulin resistance without skin aberrations in mice.

Authors:  Naoto Tsuda; Shin Kumadaki; Chika Higashi; Makoto Ozawa; Mikihiko Shinozaki; Yutaka Kato; Koutarou Hoshida; Satomi Kikuchi; Yoshihisa Nakano; Yoshihiro Ogawa; Shoji Furusako
Journal:  PLoS One       Date:  2014-11-18       Impact factor: 3.240

7.  Identification of a botanical inhibitor of intestinal diacylglyceride acyltransferase 1 activity via in vitro screening and a parallel, randomized, blinded, placebo-controlled clinical trial.

Authors:  Rodney A Velliquette; Kerry Grann; Stephen R Missler; Jennifer Patterson; Chun Hu; Kevin W Gellenbeck; Jeffrey D Scholten; R Keith Randolph
Journal:  Nutr Metab (Lond)       Date:  2015-08-06       Impact factor: 4.169
  7 in total

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