Literature DB >> 27326332

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.

Yan Shi1, Jun Li1, Lawrence J Kennedy1, Shiwei Tao1, Andrés S Hernández1, Zhi Lai1, Sean Chen1, Henry Wong1, Juliang Zhu1, Ashok Trehan1, Ngiap-Kie Lim1, Huiping Zhang1, Bang-Chi Chen1, Kenneth T Locke1, Kevin M O'Malley1, Litao Zhang1, Rai Ajit Srivastava1, Bowman Miao1, Daniel S Meyers1, Hossain Monshizadegan1, Debra Search1, Denise Grimm1, Rongan Zhang1, Thomas Harrity1, Lori K Kunselman1, Michael Cap1, Jodi Muckelbauer1, Chiehying Chang1, Stanley R Krystek1, Yi-Xin Li1, Vinayak Hosagrahara1, Lisa Zhang1, Pathanjali Kadiyala1, Carrie Xu1, Michael A Blanar1, Robert Zahler1, Ranjan Mukherjee1, Peter T W Cheng1, Joseph A Tino1.   

Abstract

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 μM) and PPARδ (EC50 > 100 μM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

Entities:  

Keywords:  Peroxisome proliferator-activated receptor (PPAR) α selective agonist; high fat fed hamster model; human ApoA1 transgenic mice; pharmacokinetics

Year:  2016        PMID： 27326332      PMCID： PMC4904259          DOI： 10.1021/acsmedchemlett.6b00033

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


  18 in total

Review 1.  Targeting peroxisome proliferator-activated receptors (PPARs): development of modulators.

Authors:  Céline Pirat; Amaury Farce; Nicolas Lebègue; Nicolas Renault; Christophe Furman; Régis Millet; Saïd Yous; Silvia Speca; Pascal Berthelot; Pierre Desreumaux; Philippe Chavatte
Journal:  J Med Chem       Date:  2012-02-27       Impact factor: 7.446

2.  Substituted 2-[(4-aminomethyl)phenoxy]-2-methylpropionic acid PPARalpha agonists. 1. Discovery of a novel series of potent HDLc raising agents.

Authors:  Michael L Sierra; Véronique Beneton; Anne-Bénédict Boullay; Thierry Boyer; Andrew G Brewster; Frédéric Donche; Marie-Claire Forest; Marie-Hélène Fouchet; Françoise J Gellibert; Didier A Grillot; Millard H Lambert; Alain Laroze; Christelle Le Grumelec; Jean Michel Linget; Valerie G Montana; Van-Loc Nguyen; Edwige Nicodème; Vipul Patel; Annie Penfornis; Olivier Pineau; Danig Pohin; Florent Potvain; Géraldine Poulain; Cécile Bertho Ruault; Michael Saunders; Jérôme Toum; H Eric Xu; Robert X Xu; Pascal M Pianetti
Journal:  J Med Chem       Date:  2007-01-23       Impact factor: 7.446

3.  Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).

Authors:  Jun Li; Lawrence J Kennedy; Yan Shi; Shiwei Tao; Xiang-Yang Ye; Stephanie Y Chen; Ying Wang; Andrés S Hernández; Wei Wang; Pratik V Devasthale; Sean Chen; Zhi Lai; Hao Zhang; Shung Wu; Rebecca A Smirk; Scott A Bolton; Denis E Ryono; Huiping Zhang; Ngiap-Kie Lim; Bang-Chi Chen; Kenneth T Locke; Kevin M O'Malley; Litao Zhang; Rai Ajit Srivastava; Bowman Miao; Daniel S Meyers; Hossain Monshizadegan; Debra Search; Denise Grimm; Rongan Zhang; Thomas Harrity; Lori K Kunselman; Michael Cap; Pathanjali Kadiyala; Vinayak Hosagrahara; Lisa Zhang; Carrie Xu; Yi-Xin Li; Jodi K Muckelbauer; Chiehying Chang; Yongmi An; Stanley R Krystek; Michael A Blanar; Robert Zahler; Ranjan Mukherjee; Peter T W Cheng; Joseph A Tino
Journal:  J Med Chem       Date:  2010-04-08       Impact factor: 7.446

Review 4.  Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease.

Authors:  Michal Pawlak; Philippe Lefebvre; Bart Staels
Journal:  J Hepatol       Date:  2014-11-01       Impact factor: 25.083

5.  High fat fed hamster, a unique animal model for treatment of diabetic dyslipidemia with peroxisome proliferator activated receptor alpha selective agonists.

Authors:  P R Wang; Q Guo; M Ippolito; M Wu; D Milot; J Ventre; T Doebber; S D Wright; Y S Chao
Journal:  Eur J Pharmacol       Date:  2001-09-21       Impact factor: 4.432

6.  A rapid, homogeneous, fluorescence polarization binding assay for peroxisome proliferator-activated receptors alpha and gamma using a fluorescein-tagged dual PPARalpha/gamma activator.

Authors:  Ramakrishna Seethala; Rajasree Golla; Zhengping Ma; Hao Zhang; Kevin O'Malley; Jonathan Lippy; Lin Cheng; Kasim Mookhtiar; Dennis Farrelly; Litao Zhang; Narayanan Hariharan; Peter T W Cheng
Journal:  Anal Biochem       Date:  2007-01-28       Impact factor: 3.365

Review 7.  Mechanism of action of fibrates on lipid and lipoprotein metabolism.

Authors:  B Staels; J Dallongeville; J Auwerx; K Schoonjans; E Leitersdorf; J C Fruchart
Journal:  Circulation       Date:  1998-11-10       Impact factor: 29.690

8.  Novel peroxisome proliferator-activated receptor alpha agonists lower low-density lipoprotein and triglycerides, raise high-density lipoprotein, and synergistically increase cholesterol excretion with a liver X receptor agonist.

Authors:  Ranjan Mukherjee; Kenneth T Locke; Bowman Miao; Daniel Meyers; Hossain Monshizadegan; Rongan Zhang; Debra Search; Denise Grimm; Michael Flynn; Kevin M O'Malley; Litao Zhang; Jun Li; Yan Shi; Lawrence J Kennedy; Michael Blanar; Peter T Cheng; Joseph Tino; Rai Ajit Srivastava
Journal:  J Pharmacol Exp Ther       Date:  2008-09-17       Impact factor: 4.030

9.  Design and synthesis of a potent and selective triazolone-based peroxisome proliferator-activated receptor alpha agonist.

Authors:  Yanping Xu; Daniel Mayhugh; Ashraf Saeed; Xiaodong Wang; Richard C Thompson; Samuel J Dominianni; Raymond F Kauffman; Jaipal Singh; James S Bean; William R Bensch; Robert J Barr; John Osborne; Chahrzad Montrose-Rafizadeh; Richard W Zink; Nathan P Yumibe; Naijia Huang; Debra Luffer-Atlas; Deepa Rungta; Dale E Maise; Nathan B Mantlo
Journal:  J Med Chem       Date:  2003-11-20       Impact factor: 7.446

Review 10.  Saroglitazar for the treatment of hypertrig-lyceridemia in patients with type 2 diabetes: current evidence.

Authors:  Aravind Sosale; Banshi Saboo; Bhavana Sosale
Journal:  Diabetes Metab Syndr Obes       Date:  2015-04-15       Impact factor: 3.168
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